Methods, compositions, and systems to treat chronic disease through cellular reprogramming

Abstract

The present disclosure concerns methods and compositions related to reprogramming cellular functions. Such compositions are cellular reprogramming proteins comprising two polypeptides and a human Fc domain. The cellular reprogramming protein can additional comprise an appended domain. Embodiments include using the protein or a DNA / RNA encoding the protein in the therapy of immune diseases such as fibrosis and Castleman disease. Other example uses include, for example, suppressing irAEs associated with cancer immunotherapy including fibrosis, suppressing irAEs associated with cancer cell therapies (CAR-T, etc.), targeting immuno-senescence to improve cancer vaccine and general vaccine efficacy, treating inflammation-driven diseases (e.g., MASH, NASH, SLE, psoriasis, RA, etc.), treating GVHD in AML, treating or preventing radiation induced fibrosis, inflammatory cardiovascular, and inflammatory neurodegenerative diseases.

Description

METHODS, COMPOSITIONS, AND SYSTEMS TO TREAT CHRONIC DISEASE THROUGH CELLULAR REPROGRAMMING CLAIM OF PRIORITY

[0001] This application claims the benefit of U.S. Provisional Application 63 / 752,408, filed on January 31, 2025, which is incorporated by reference in full herein.

[0002] The application contains a Sequence Listing in compliance with ST.26 format and is hereby incorporated by reference in its entirety. Said Sequence Listing, created on January 30, 2026 is named MDACP1417WO_xml and is 45,775 bytes in size.TECHNICAL FIELD

[0003] The present disclosure relates generally at least to the fields of immunology, cell biology, molecular biology, and medicine.BACKGROUND

[0004] Acute inflammatory processes are necessary to fend off infection and provide essential protective response to injured tissues, however, when the body fails to fully return to homeostasis, persistent inflammation leads to multiple debilitating diseases (chronic pain, neurodegeneration, and fibrosis, to name a few). While there are several anti-inflammatory medications that help bring patients out of the acute inflammatory response and into chronic management (e.g., anti-TNFa, Abatacept, Dexamethasone), long-term use of these agents leaves patients highly vulnerable to other emerging chronic illness states, lethal infections, malignancies and autoimmune diseases, including cancer and cardiovascular disease. Further challenges relate to immune-related adverse events (irAEs) associated with cancer immunotherapy, including fibrosis, irAEs associated with cancer cell therapies (CAR-T, etc.), immuno-senescence to improve cancer vaccine and general vaccine efficacy, treating chronic inflammation-driven diseases (e.g., MASH, NASH, SLE, psoriasis, RA, etc.), treating GVHD, treating or preventing radiation-induced fibrosis, and inflammatory neurodegenerative diseases. Management of chronic illness, toxicides derived from current medications, and avoiding emergence of secondary chronic illness is a major unmet need in biomedicine, having a great impact on human health.

[0005] Reports of irAEs continue to rise as significant progress is made to re-engage the immune system through immunotherapy, targeted cell-based therapies, and combinatorial 301645057.1therapies for cancer patients, however this means that these heavily treated patient populations often receive additional immunosuppressants leaving them susceptible to life-threatening infections. In some reports up to 20-30% of patients with severe irAEs can have infection-related mortality.

[0006] More than 50% of cancer patients receive external beam radiation as part of their treatment course, and it is estimated that 30% go on to develop severe radiation-induced fibrosis. Radiation-induced fibrosis (RIF) is a long-term side effect of radiation therapy used in the treatment of cancer. Marked by replacement of normal tissue with matrix and disorganized and varied collagen fibrils, RIF results in loss of organ function, frequent tissue contraction leading to death, or significant deterioration in the quality of life for many patients.

[0007] Disruptions in the lymphatic system, both in connectivity and flow, yield significant morbidity and mortality across a variety of diseases. While chemo-radiation, radiotherapy and immunotherapy combined with radiation are important treatment advances saving lives, they also often are accompanied with long-term side effects, including disruption of the lymphatic system. When radiotherapy damages the lymph nodes, they can become fibrotic and impair their ability to drain lymphatic fluid leading to lymphedema and the development of hard, scar-like tissue in the treated area due to excessive collagen production; this can significantly impact tissue function and mobility. Radiation-induced fibrosis (RIF) and disruption of the lymphatic system can lead to death, morbidity, and cancer risk, dramatically impacting quality of life for survivors of acute radiation toxicity.

[0008] While typical anti-inflammatories can radically inhibit the acute phase of inflammation their ability to reverse fibrosis and deliver a sufficient therapeutic index is inadequate likely since potent inhibition of the immune system also turns off key effector cells (e.g. neutrophils) that are required to degrade fibers and reset the system to homeostasis / final healing. This imbalance hinders the ability of the host immune system to fight infection, tumorigenesis and resolve fibrosis and thus lymphatic function is continuously and chronically reduced. Reduced lymphatic communication with the site may indeed further exacerbate fibrosis by inhibiting its resolution by the innate immune system in a vicious negative feedback loop. Thus, there is the need to develop a scalable, acute intervention to ameliorate RIF after exposure and after the initial induction of fibrosis.301645057.1SUMMARY

[0009] Embodiments of the disclosure relate to a cellular reprogramming protein comprising, in order, a first polypeptide, a second polypeptide, and a third polypeptide, wherein the first polypeptide, second polypeptide, and third polypeptide are selected from the group consisting of Human Fc domain, B7 protein, CD80, CD83, CD86, ICOS, MHC-I, MHC-II, CD40, IL-18, IL-37, TNF-alpha, INF-gamma, cytokines, IL-15, HLA-F, CD19, CD4, HLA-B, IL-17RB, and TGF-beta, and wherein the cellular reprogramming protein comprises exactly one human Fc domain. In embodiments, the human Fc domain is IgE, IgA, IgM, IgE, IgD, IgG3, IgE, IgA, IgGl-Act, IgGl-LALA, or IgGl. In some embodiments, the B7 protein is B7-H3, B7-H2, B7-DC, B7-H4, B7-H6, or B7-H7. The Fc domain can be an activating mutant or an inhibitory mutant. In embodiments, the protein comprises a first linker sequence of amino acids between the first polypeptide and the second polypeptide, and wherein the protein comprises a second linker sequence of amino acids between the second polypeptide and the third polypeptide. In embodiments, the first linker sequence and / or the second linker sequence comprises the amino acid sequence GGGSx4. In embodiments, wherein the first polypeptide is IgGl, the second polypeptide is 41g-B7H3, and the third polypeptide is 21g-B7H3. In embodiments, wherein the protein is at least 80% similar to SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, with or without a signaling peptide and / or with or without a His tag. In embodiments, wherein the first polypeptide is IgE, the second polypeptide is 21g-B7-H3, and the third polypeptide is IL15. In embodiments, the first polypeptide is IgA, the second polypeptide is HLA-F, and the third polypeptide is CD4. In embodiments, the first polypeptide is IgM, the second polypeptide is CD19, and the third polypeptide is CD4. In embodiments, the first polypeptide is IgE, the second polypeptide is HLA-B, and the third polypeptide is B7-H4 (VTCN1). In embodiments, the first polypeptide is IgD, the second polypeptide is HLA-B, and the third polypeptide is CD80. In embodiments, the first polypeptide is IgG3, the second polypeptide is IL25, and the third polypeptide is CD274. In embodiments, the first polypeptide is IgE, the second polypeptide is TNFa, and the third polypeptide is TFG-B. In embodiments, the first polypeptide is IgA, the second polypeptide is IL-15, and the third polypeptide is IL-17RB. In embodiments, the first polypeptide is IgGl-Act, the second polypeptide is 41g B7-H3, and the third polypeptide is 21g-B7-H3. In embodiments, the first polypeptide is IgGl-LALA, the second polypeptide is 41g B7-H3, and the third polypeptide is 21g-B7-H3. In embodiments, the first polypeptide is 41g B7-H3, the second polypeptide is IgGl, and the third polypeptide is 21g-B7-H3. In301645057.1embodiments, the first polypeptide is 41g B7-H3, the second polypeptide is 21g-B7-H3, and the third polypeptide is IgGl. In embodiments, the cellular reprogramming protein additionally comprises one or more of p28 (azurin fragment), Flagellin and derivatives, Ac SDKP, Humanin, MOTS c, LL 37, C peptide fragment, Thymosin P4 fragment, GLP1, GIP, GLP 2 fragment, Apelin 13, KPV, VIP fragment, Uroguanylin fragment, Kisspeptin 10, PTH(1-14), BDNF mimetic GSB 106, GHK Cu, Melanotan II fragment, Thymosin al fragment, a MSH KPV, Defensin fragment, Thymosin p4(l-4), NPY13 36, Endomorphin 1, and / or Histatin 5 fragment on an end terminus. The protein can further comprising a bifunctional chelate. Embodiments also include nucleic acid molecule comprising a nucleotide sequence encoding a protein as defined anywhere in this paragraph. Some embodiments include modulating cellular processes in an individual by administering to the individual the protein as defined anywhere in this paragraph. In some embodiments, the individual has been previously treated for cancer. In embodiments, the individual has inflammation, lymphedema, fibrosis, Castleman disease, lymphatic dysfunction, cancer, neurodegeneration, deconditioning, viral latency and reactivation, metabolic dysfunction, barrier dysfunction, digestive disorders, cardiovascular disease, wound healing, respiratory disease, urinary and excretory system disorders, infertility, osteoporosis and fracture, hearing loss, cosmetic applications, sexual dysfunction, immunosenescence, chronic and recurrent infectious diseases, regenerative and transplant medicine, psychosis disorders, chronic pain, autoimmune disease, and / or microbial response.

[0010] Another embodiment of the disclosure is a computer implemented method of identifying a cellular reprogramming protein that reprograms the cellular processes of an individual in need thereof comprising: generating a set of protein sequences comprising in order, a first polypeptide, a second polypeptide, and a third polypeptide, wherein the first polypeptide, second polypeptide, and third polypeptide are selected from the group consisting of Human Fc domain, B7 protein, CD80, CD83, CD86, ICOS, MHC-I, MHC-II, CD40, IL- 18, IL-37, TNF-alpha, INF-gamma, cytokines, IL-15, HLA-F, CD19, CD4, HLA-B, IL-17RB, and TGF-beta, and wherein the immunomodulating polypeptide comprises exactly one human Fc domain; generating a protein with a sequence from the at least one of the set of protein sequences; testing the generated protein for activity.

[0011] Another embodiment of the disclosure is a computer implemented method for producing cellular reprogramming proteins using an analytics module executed by a processor301645057.1of a computer system, the method comprising: receiving, by the analytics module from a computer data storage system, at least one Fc domain identifier and a plurality of extracellular polypeptide identifiers; sampling, by the analytics module executed by the processor, constructs comprising at least one of the identified Fc domains and at least two of the identified polypeptides, for each sampled construct calculate if it is orthogonal or divergent; transmitting at least one of the constructs to a machine, wherein the at least one selected construct is selected based on its orthogonality; creating a synthetic protein with the selected sequence. In embodiments, the synthetic protein is tested for immune modulation. In embodiments, the protein is tested for anti-inflammatory properties. In embodiments, the synthetic protein is tested for cellular response to cancer, fibrosis, neurodegeneration, deconditioning, viral latency and reactivation, metabolic dysfunction, barrier dysfunction, digestive disorders, cardiovascular disease, wound healing, respiratory disease, urinary and excretory system disorders, infertility, osteoporosis and fracture, hearing loss, cosmetic applications, sexual dysfunction, immunosenescence, chronic and recurrent infectious diseases, regenerative and transplant medicine, psychosis disorders, chronic pain, autoimmune disease, and microbial response. In embodiments, the synthetic protein comprise a plurality of sequences with, in order, a first polypeptide, a second polypeptide, and a third polypeptide, wherein the first polypeptide, second polypeptide, and third polypeptide are selected from the group consisting of Human Fc domain, B7 protein, CD80, CD83, CD86, ICOS, MHC-I, MHC-II, CD40, IL- 18, IL-37, TNF-alpha, INF-gamma, cytokines, IL-15, HLA-F, CD19, CD4, HLA-B, IL-17RB, and TGF-beta, and wherein each protein sequence comprises exactly one human Fc domain. In embodiments, the synthetic protein is created using recombinant protein expression. In embodiments, the recombinant protein expression is automated from receipt of the selected sequence. In embodiments, the synthetic protein is created using solid-phase peptide synthesis. In embodiments, the solid-phase peptide synthesis is automated from receipt of the transmitted selected sequence. In embodiments, sampling comprises a machine learning method.

[0012] Additional embodiments of the disclosure include a non-transitory computer-readable storage medium having computer-executable instructions stored thereon, which when executed by one or more processors, causes the one or more processors to perform operations comprising: (a) receiving at least one Fc domain identifier and a plurality of extracellular polypeptide identifiers; (b) sample constructs comprising one Fc domain and at least two polypeptides; (c) for each sample construct, calculating if it is orthogonal or divergent; (d) transmitting at least one construct, wherein the construct is selected based orthogonality. In301645057.1embodiments, sampling and / or calculating comprises a machine learning method. In embodiments, the set of protein sequences comprises a plurality of sequences with, in order, a first polypeptide, a second polypeptide, and a third polypeptide, wherein the first polypeptide, second polypeptide, and third polypeptide are selected from the group consisting of Human Fc domain, B7 protein, CD80, CD83, CD86, ICOS, MHC-I, MHC-II, CD40, IL- 18, IL-37, TNF-alpha, INF-gamma, cytokines, IL-15, HLA-F, CD19, CD4, HLA-B, IL-17RB, and TGF-beta, and wherein each protein sequence comprises exactly one human Fc domain. In embodiments, the calculating is based on a dimensionally reduced representation of the sequence and associated amino acid charge, polarity, rarity, hydrophobicity, steady state plasma levels, and / or known multimerization states of their antibody isotype. In embodiments, a ranked order of orthogonally identified constructs is transmitted. In embodiments, the Fc domain identifiers and / or the extracellular polypeptide identifiers are identified by name and / or sequence.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The following drawings throughout this disclosure form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0014] FIG. 1 depicts an example of a modular design of an cellular reprogramming protein library, where circular permutations engender novel constructs.

[0015] FIG. 2 depicts an example of a library member which consists of three domains. Fc = Human Fc domains (e.g., IgGl, IgG2, IgM); X = Fc mutation (e.g., inhibitory or activating); B = B7 family member, extracellular domain starting with 4Ig-B7-H3; C = B7 family member extracellular domain or other Ig or small cytokine or null. Between the domains is a linker (e.g., (GGGS)x4).

[0016] FIG. 3 depicts a dot product matrix of the unit descriptor vector for the first 100 constructs selected to be orthogonal to PI- 1-4-2 (dark gray -1, light gray +1) (top). The diagonal is +1 by definition. Image-based orthogonality and library clustering in 3-dimensional space is also depicted (bottom). PL 1-4-2 is the most bottom right circle, other differentiated constructs are indicated in other circles.301645057.1

[0017] FIG. 4 is an amino acid sequence of IgGl Fc-4IgB7H3-2IgB7H3 (SEQ ID NO: 1).

[0018] FIG. 5 shows images of SDS-PAGE (left) and Western blot (right) of PI- 1-4-2. Lane Mi: Protein marker, Bio-rad, Cat. No. 1610374S, refer to annotated key of the left for size. Lane M2: Protein marker, GeneScript, Cat. No. M00673, refer to annotated key on the left for size. R: Reducing condition. NR: Non-reducing condition. Lane P: Human IgGl, Kappa (Sigma, Cat. No. 15154) as a positive control. Primary antibody: Goat anti-human IgG(H+L)-HRP (Southembiotech, Cat. No. 2015-05).

[0019] PIG. 6 shows size exclusion chromatography results of cloned and produced PI-1-4-2.

[0020] PIG. 7 shows an amino acid sequence of IgG2 Pc-2IgB7H3-PDL2 (SEQ ID NO: 2). This construct is also known as PI-2-2-2, PL2-2-PDL2, and PI222.

[0021] PIG. 8 shows images of SDS-PAGE (left) and Western blot (right) of IgG2 Pc-2IgB7H3-PDL2. Lane Ml: Protein marker, Bio-rad, Cat. No. 1610374S, refer to annotated key of the left for size. Lane M2: Protein marker, GeneScript, Cat. No. M00673, refer to annotated key on the left for size. R: Reducing condition. NR: Non-reducing condition. Lane P: Human IgGl, Kappa (Sigma, Cat. No. 15154) as a positive control. Primary antibody: Goat anti-human IgG(H+L)-HRP (Southernbiotech, Cat. No. 2015-05).

[0022] PIG. 9 shows size exclusion chromatography results of cloned and produced IgG2 Pc-2IgB7H3-PDL2.

[0023] PIG. 10 shows oxidative burst results of THP-1 cells polarized to Ml state in presence of B7 library biologies.

[0024] PIGS. 11A-11C show bioluminescent Salmonella growth in the presence of THP-1 macrophage-like cells that were pre-treated with diluent or anti-inflammatories for 4-24 hrs. Photon flux was measured using a CCD camera at 1 second exposure of FL6 Salmonella (genetically modified Salmonella that are constitutively bioluminescent) alone or in the presence of THP-1 cells for 0-30 minutes. Intracellular and extracellular bacteria were quantified over time. FIG. 11A shows results from THP-1 cells were pre-treated for 4 hours with 30 pM PL 1-4-2, Abatacept, or Dexamethasone prior to incubation with Salmonella. FIG.301645057.11 IB shows results from THP-1 cells that were pre-treated for 24 hours with 30 pM PI-1-4-2, Abatacept, or Dexamethasone prior to incubation with Salmonella. FIG. 11C shows change of bioluminescence over time, reflecting bacteria killing ability of THP- 1 cells that were pretreated for 24 hours with the anti-inflammatories. FIG. 1 ID is a graphical representation of the slope that was determined for each treatment group in FIG. 11C.

[0025] FIG. 12 shows RONS burst results in SGM3 mice, a model of neuroinflammation, treated with PI- 1-4-2. Weekly intraperitoneal injection of 200 pg of PI- 1-4-2 or PBS were administered to SGM3 mice. L-012 cranial signal was detected at baseline and monitored over the course of the study by BLI.

[0026] FIG. 13 shows cranial RONS bursts prior to (Day 0), during treatment for two weeks, and following weekly treatment with PI-1-4-2 (200 pg). Treatment ended on Day 20, but low cranial BLI signal (low RONS bursts) were maintained for at least another two weeks.

[0027] FIG. 14 is a graphical representation of the survival probability of Hu-SMG3 HLH mice post treatment with PI- 1-4-2. Treatment with PL 1-4-2 for two weeks and then removed, significantly improved survival for HLH, humanized mice.

[0028] FIGS. 15A-15D depict an experimental procedure for testing and assessing PBMCs treated with PL 1-4-2. FIG. 15 A is a schematic of the collection and isolation of patient PBMCs that were treated ex-vivo with diluent or PL1-4-2 (20 nM). FIG. 15B shows results of RONS bursts measured by L-012 imaging of PBMCs 0-24 hours post treatment. FIG. 15C shows quantification of the relative change in RONS bursts following treatment with 20 nM PL1-4-2 over 0-24 hrs. FIG. 15D shows relative change in RONS bursts vs. cell viability following 24 hr treatment and ex-vivo culture of primary HLH patient PBMCs. The experiment was completed in technical quadruplicate.

[0029] FIGS. 16A-16E show NASH-induced Fibrosis and Liver Inflammation. FIG.16A is a schematic of experimental design, including treatment IX weekly, intermittent imaging, and endpoint analysis of tissue. FIG. 16B show images of PicroSirius red staining performed on endpoint FFPE fixed livers and quantification of fibrosis as determined by the fraction of PicroSirius red high area per field. FIG. 16C show images of H&E staining of endpoint livers. Scale bars indicate 5-10 pm and 100 pm for zoomed image. FIG. 16D is a graph of change in body weight over the course of the treatment measured for each mouse.301645057.1FIG. 16E is a graph of liver pseudo density of each endpoint liver, determined by measuring the tumor weight (g) over the area (cm2).

[0030] FIGS. 17A-17C show F4 / 80 staining of endpoint livers. FIG. 17A shows macro and micro images of F4 / 80 staining of PBS-treated or PI-l-4-2-treated endpoint livers. Scale bars indicate 5-10 pm and 100 pm for zoomed images. FIG. 17B shows representative images of F4 / 80 crown-like structures or F4 / 80 clusters. Scale bar represents 200 pm. FIG. 17C is a graph of the quantification of F4 / 80 crown and cluster structures as measured per 5 fields for each treated mouse.

[0031] FIG. 18 shows a summary of PI- 1-4-2 demonstrating how a library member can turn a diseased system on a trajectory towards homeostasis.

[0032] FIG. 19 shows the amino acid sequence of IgE_2Ig-B7-H3_IL15.

[0033] FIG. 20 shows an image of SDS-PAGE of cloned IgE_2Ig-B7-H3_IL15.

[0034] FIG. 21 shows size exclusion chromatography results of cloned IgE_2Ig-B7-H3_IL15.

[0035] FIG. 22 shows the amino acid sequence of IgA-HLA-F-CD4.

[0036] FIG. 23 shows an image of SDS-PAGE of cloned IgA-HLA-F-CD4.

[0037] FIG. 24 shows an image of Western blot of cloned IgA-HLA-F-CD4.

[0038] FIG. 25 shows size exclusion chromatography results of cloned IgA-HLA-F-CD4.

[0039] FIG. 26 shows the amino acid sequence of IgM-CD19-CD4.

[0040] FIG. 27 shows an image of SDS-PAGE of cloned IgM-CD19-CD4.

[0041] FIG. 28 shows an image of Western blot of cloned IgM-CD19-CD4.

[0042] FIG. 29 shows size exclusion chromatography results of cloned IgM-CD19-CD4.

[0043] FIG. 30 shows the amino acid sequence of IgE-HLA-B-B7-H4 (VTCN1).301645057.1

[0044] FIG. 31 shows an image of SDS-PAGE of cloned IgE-HLA-B-B7-H4 (VTCN1).

[0045] FIG. 32 shows an image of Western blot of cloned IgE-HLA-B-B7-H4 (VTCN1).

[0046] FIG. 33 shows size exclusion chromatography results of cloned IgE-HLA-B-B7-H4 (VTCN1).

[0047] FIG. 34 shows the amino acid sequence of IgD-HLA-B-CD80.

[0048] FIG. 35 shows an image of SDS-PAGE of cloned IgD-HLA-B-CD80.

[0049] FIG. 36 shows size exclusion chromatography results of cloned IgD-HLA-B-CD80.

[0050] FIG. 37 shows the amino acid sequence of IgG3-IL25-CD274.

[0051] FIG. 38 shows an image of SDS-PAGE of cloned IgG3-IL25-CD274.

[0052] FIG. 39 shows size exclusion chromatography results of cloned IgG3-IL25-CD274.

[0053] FIG. 40 shows the amino acid sequence of IgE-TNFa-TGF-B.

[0054] FIG. 41 shows an image of SDS-PAGE of cloned IgE-TNFa-TGF-B.

[0055] FIG. 42 shows an image of Western blot of cloned IgE-TNFa-TGF-B.

[0056] FIG. 43 shows size exclusion chromatography results of cloned IgE-TNFa-TGF-B.

[0057] FIG. 44 shows the amino acid sequence of IgA-IL-15-IL-17RB.

[0058] FIG. 45 shows an image of SDS-PAGE of cloned IgA-IL-15-IL-17RB.

[0059] FIG. 46 shows an image of Western blot of cloned IgA-IL-15-IL-17RB.

[0060] FIG. 47 shows size exclusion chromatography results of cloned IgA-IL-15-IL- 17RB.301645057.1

[0061] FIG. 48 shows the amino acid sequence of IgGl-Act-4Ig B7-H3-2Ig-B7-H3.

[0062] FIG.49 shows an image of SDS-PAGE of cloned IgGl-Act-4Ig B7-H3-2Ig-B7-H3.

[0063] FIG. 50 shows size exclusion chromatography results of cloned IgGl-Act-4Ig B7-H3-2Ig-B7-H3.

[0064] FIG. 51 shows a schematic of IgGl-Act-4Ig B7-H3-2Ig-B7-H3.

[0065] FIG. 52 shows the amino acid sequence of IgGl- LALA-4Ig B7-H3-2Ig-B7-H3.

[0066] FIG. 53 shows an image of SDS-PAGE of cloned IgGl- LALA-4Ig B7-H3-2Ig-B7-H3.

[0067] FIG. 54 shows size exclusion chromatography results of cloned IgGl- LALA-41g B7-H3-2Ig-B7-H3.

[0068] FIG. 55 shows a schematic of IgGl- LALA-4Ig B7-H3-2Ig-B7-H3.

[0069] FIG. 56 shows the amino acid sequence of 4IgB7-H3-IgGl-2Ig-B7-H3.

[0070] FIG. 57 shows an image of SDS-PAGE of cloned4IgB7-H3-IgGl-2Ig-B7-H3.

[0071] FIG. 58 shows size exclusion chromatography results of cloned4IgB7-H3-IgGl-2Ig-B7-H3.

[0072] FIG. 59 shows a schematic of 4IgB7-H3-IgGl-2Ig-B7-H3.

[0073] FIG. 60 shows the amino acid sequence of 4Ig-B7-H3_2Ig-B7-H3_IgGl.

[0074] FIG. 61 shows an image of SDS-PAGE of cloned4Ig-B7-H3_2Ig-B7-H3_IgGl.

[0075] FIG. 62 shows size exclusion chromatography results of cloned4Ig-B7-H3_2Ig- B7-H3_IgGl.

[0076] FIG. 63 shows a schematic of 4Ig-B7-H3_2Ig-B7-H3_IgGl.301645057.1

[0077] FIG. 64 depicts RONS burst of Ml -polarized macrophages after treatment with PMA and Pl-constructs.

[0078] FIG. 65 shows graphs representing relative total flux 24 hours post treatment with PMA and Pl-constructs.

[0079] FIG. 66 depicts RONS burst of M2c-polarized macrophages after treatment with PMA and Pl-constructs.

[0080] FIG. 67 shows graphs representing relative total flux 24 hours post treatment with PMA and Pl-constructs.

[0081] FIG. 68 shows schematics of PI-1-4-2, PI-4-1-2, and PI-4-2-1.

[0082] FIG. 69 shows relative total flux over M2 polarization.

[0083] FIG. 70 depicts an example of a modular design of an cellular reprogramming protein library with one or more end terminal additions, such as proteins, peptides, small molecules or c-terminus adducts.

[0084] FIG. 71 depicts an example of a modular design of an cellular reprogramming protein library with a linker and peptide adduct (e.g. GLP1 or GIP).

[0085] FIG. 72 is an exemplary computer system of the disclosure.

[0086] FIG. 73 is a description of an example protein of the disclosure, PI-l-PDCD- IL37.

[0087] FIG. 74 is a description of an example protein of the disclosure, PI-lAct-25-B2M.

[0088] FIG. 75 is a description of an example protein of the disclosure, PI-4-CD19-HLAB.

[0089] FIG. 76 is a description of an example protein of the disclosure, PI-2-2-HLAF-1.

[0090] FIG. 77 is a description of an example protein of the disclosure, PI-1LALA- HLAF-1-CD80.301645057.1

[0091] FIG. 78 is a description of an example protein of the disclosure, PI-4-HLAB-CD86.

[0092] FIG. 79 is a description of an example protein of the disclosure, PI-2-CD19-CD86.

[0093] FIG. 80 is a description of an example protein of the disclosure, PI-3-CD4-CD8A.

[0094] FIG. 81 is a description of an example protein of the disclosure, PI-2-4-HLAC.

[0095] FIG. 82 is a description of examples of PI constructs from Figs. 73-81.

[0096] FIG. 83A is a description of an example protein of the disclosure, PI-l-PDCD-IL37.

[0097] FIG. 83B depicts a SDS-PAGE gel of an example protein of the disclosure, PI-1-PDCD-IL37. Lane M: Protein Marker, R: Reducing condition, NR: Non-reducing condition.

[0098] FIG. 83C depicts a Western blot of an example protein of the disclosure PI-1-PDCD-IL37. Lane M: Protein Marker, R: Reducing condition, NR: Non-reducing condition, Primary antibody: Goat Anti-Human IgG(H+L)-HRP (Left), Primary antibody: Mouse-anti-His mAb (Right).

[0099] FIG. 83D depicts SEC-HPLC data of an example protein of the disclosure, PI-1-PDCD-IL37.

[0100] FIG. 84A is a description of an example protein of the disclosure, PL4-CD19-HLAB.

[0101] FIG. 84B depicts a SDS-PAGE gel of an example protein of the disclosure, PI-4-CD19-HLAB. Lane M: Protein Marker, R: Reducing condition, NR: Non-reducing condition.

[0102] FIG. 84C depicts SEC-HPLC data of an example protein of the disclosure, PI-4-CD19-HLAB.

[0103] FIG. 85A is a description of an example protein of the disclosure, PI-2-2-HLAF- 1.301645057.1

[0104] FIG. 85B depicts a SDS-PAGE gel of an example protein of the disclosure, PI-2-2-HLAF-l. Lane M: Protein Marker, R: Reducing condition, NR: Non-reducing condition.

[0105] FIG. 85C depicts Western blots of an example protein of the disclosure, PI-2-2-HLAF-1. Lane M: Protein Marker, R: Reducing condition, NR: Non-reducing condition. Primary antibody: Goat Anti-Human IgG(H+L)-HRP (Left), Primary antibody: Mouse-anti-His mAb (Right)

[0106] FIG. 85D depicts SEC-HPLC data of an example protein of the disclosure, PI-2-2-HLAF-l.

[0107] FIG. 86A is a description of an example protein of the disclosure, PI-1LALA-HLAF-1-CD80.

[0108] FIG. 86B depicts a SDS-PAGE gel of an example protein of the disclosure, PI-1LALA-HLAF-1-CD80. PI-2-2-HLAF-1. Lane M: Protein Marker, R: Reducing condition, NR: Non-reducing condition.

[0109] FIG. 86C depicts Western blots of an example protein of the disclosure, PI-1LALA-HLAF-1-CD80. PI-2-2-HLAF-1. Lane M: Protein Marker, R: Reducing condition, NR: Non-reducing condition. Primary antibody: Goat Anti-Human IgG(H+L)-HRP (Left), Primary antibody: Mouse-anti-His mAb (Right).

[0110] FIG. 86D depicts SEC-HPLC data of an example protein of the disclosure, PI-1LALA-HLAF-1-CD80.

[0111] FIG. 87A is a description of an example protein of the disclosure, PI-1LALA-HLAF-1-CD80.

[0112] FIG. 87B depicts a SDS-PAGE gel of an example protein of the disclosure, PI-1LALA-HLAF-1-CD80. Lane M: Protein Marker, R: Reducing condition, NR: Non-reducing condition.

[0113] FIG. 87C depicts Western blots of an example protein of the disclosure, PI-1LALA-HLAF-1-CD80. Lane M: Protein Marker, R: Reducing condition, NR: Non-reducing condition. Primary antibody: Goat Anti-Human IgG(H+L)-HRP (Left), Primary antibody: Mouse-anti-His mAb (Right).301645057.1

[0114] FIG. 87D depicts SEC-HPLC data of an example protein of the disclosure, PI-1LALA-HLAF-1-CD80.

[0115] FIG. 88A is a description of an example protein of the disclosure, PI-4-HLAB-CD86.

[0116] FIG. 88B depicts a SDS-PAGE gel of an example protein of the disclosure, PI-4-HLAB-CD86. Lane M: Protein Marker, R: Reducing condition, NR: Non-reducing condition.

[0117] FIG. 88C depicts SEC-HPLC data of an example protein of the disclosure, PI-4-HLAB-CD86.

[0118] FIG. 89A is a description of an example protein of the disclosure, PI-2-CD19-CD86

[0119] FIG. 89B depicts a SDS-PAGE gel of an example protein of the disclosure, PI-2-CD19-CD86. Lane M: Protein Marker, R: Reducing condition, NR: Non-reducing condition.

[0120] FIG. 89C depicts SEC-HPLC data of an example protein of the disclosure, PI- 2-CD19-CD86.

[0121] FIG. 90A is a description of an example protein of the disclosure, PI-3-CD4-CD8A.

[0122] FIG. 90B depicts a SDS-PAGE gel of an example protein of the disclosure, PI- 3-CD4-CD8A. Lane M: Protein Marker, R: Reducing condition, NR: Non-reducing condition.

[0123] FIG. 90C depicts SEC-HPLC data of an example protein of the disclosure, PI-3-CD4-CD8A.

[0124] FIG.91 A is a description of an example protein of the disclosure, PI-2-4-HLAC.

[0125] FIG. 9 IB depicts a SDS-PAGE gel of an example protein of the disclosure, PI-2-4-HLAC. Lane M: Protein Marker, R: Reducing condition, NR: Non-reducing condition.

[0126] FIG. 91C depicts Western blots of an example protein of the disclosure, PI-2-4-HLAC. Lane M: Protein Marker, R: Reducing condition, NR: Non-reducing condition. Primary301645057.1antibody: Goat Anti-Human IgG(H+L)-HRP (Left), Primary antibody: Mouse-anti-His mAb (Right).

[0127] FIG. 9 ID depicts SEC-HPLC data of an example protein of the disclosure, PI-2-4-HLAC.

[0128] FIG. 92 depicts a process for assessment of antibody developability used for several proteins of the disclosure.

[0129] FIG. 93 depicts size-exclusion high performance liquid chromatography (SE-HPLC) results of various proteins of the disclosure to characterize aggregation of protein biologies by separating and quantifying molecular species such as aggregates, monomers, dimers, and degradation products based on their hydrodynamic size.

[0130] FIG. 94 depicts hydrophobic interaction chromatography (HIC) results of various proteins of the disclosure to assess hydrophobicity of protein biologies by measuring their retention time on a hydrophobic matrix.

[0131] FIG. 95 depicts standup monolayer absorption chromatography (SMAC) results of various proteins of the disclosure to assess colloidal stability or hydrophobicity of protein biologies based on their affinity to a solid-phase monolayer (mixed-mode matrix) for differentiation based on binding strength and surface interactions.

[0132] FIG. 96 depicts Heparin Affinity Chromatography (HAC) results of various proteins of the disclosure to assess heparin binding. In this method, HAC separates molecules based on their affinity to heparin, a sulfated glycosaminoglycan immobilized on a solid-phase support, which allows for differentiation of molecules based on their binding strength to heparin and providing insights into their non-specific surface interactions and implications on pharmacokinetics.

[0133] FIG. 97 depicts thermostability results from using nanoDSF using a SUPR-DSF instrument (Protein Stable) with a temperature ramp of 1 °C / min from 20 °C to 100 °C. nanoDSF uses the intrinsic fluorescence of aromatic residues (Tyr, Trp) to measure protein unfolding. The resulting fluorescence ratio (350 / 330 nm) is plotted as a function of temperature, and the data are fit to a sigmoidal curve to determine the thermal transition midpoint (Tm).301645057.1

[0134] FIG. 98 depicts self-association results of various proteins of the disclosure that were measured by gold nanoparticle plasmon shift. For the gold nanoparticle plasmon shift, gold nanoparticles are coated with anti-IgG capture antibodies and incubated with samples of purified protein biologies. The absorbance is read from 450-650 nm and the difference in the wavelength of max absorbance between the sample and the buffer is reported.

[0135] FIG. 99 depicts polyreactivity results of various proteins of the disclosure that were measured by flow cytometry for nonspecific binding to CHO cell lysate. This method utilizes magnetic beads to immobilize protein biologies followed by incubation with the polyreactive reagent. A PR (polyreactivity) score for each sample is calculated by normalizing its median fluorescence intensity against those for known low, medium, and high polyreactive protein biologies. PR scores are reported on a scale of 0-1 with 1 indicating high polyreactivity.

[0136] FIG. 100 depicts FcRn binding (BLI) results of various proteins of the disclosure, for their binding affinity to the human neonatal Fc receptor (FcRn). The method includes immobilizing biotinylated recombinant human FcRn on streptavidin-coated Octet biosensors and measuring the change in reflected light caused by protein biologic binding. The resulting data is then used to calculate the dissociation constant (KD), which quantifies the strength of the protein biologic-FcRn interaction.

[0137] FIG. 101 depicts the process for preparing polarized human monocytes with proteins of the disclosure for RNA sequencing analysis and respiratory burst analysis.

[0138] Figs. 102A and B depict a heatmap of differentially expressed genes between Ml -like polarized human primary macrophages treated with diluent, PI- 1-4-2, PI-2-2-PDL2 and PI-4-2-1. FIG. 102 A is the full heat map and FIG. 102B is zoomed into the marked portion of FIG. 102 A.

[0139] FIG. 103 A and B depict a heatmap of differentially expressed genes between Ml -like polarized human primary macrophages treated with diluent, PI- 1-4-2, PI-2-2-PDL2 and PI-4-2-1. FIG. 103 A is the full heat map and FIG. 103B is zoomed into the marked portion of FIG. 103 A.

[0140] FIG. 104 depicts a heatmap of differentially expressed genes between Ml -like polarized human primary macrophages treated with diluent, PI- 1-4-2, PI-2-2-PDL2 and PI-4-2-1.301645057.1

[0141] FIG. 105 depicts a barplot of enriched gene ontology (GO) terms of differentially expressed genes between Ml -like polarized macrophages treated with diluent, PI- 1-4-2, PI-2-2-PDL2 and PI-4-2-1.

[0142] FIG. 106 depicts a scatterplot of enriched GO terms of differentially expressed genes between Ml -like polarized macrophages treated with diluent, PI- 1-4-2, PI-2-2-PDL2 and PI-4-2-1.

[0143] FIG. 107A and B depict a heatmap of differentially expressed genes between M2-like polarized human primary macrophages treated with diluent, PI-2-2-PDL2, PI-3-25-274 and PI-E-2-15. FIG. 107 B is the zoomed in portion that is marked in FIG. 107A.

[0144] FIG. 108A and B depict a heatmap of differentially expressed genes between M2-like polarized human primary macrophages treated with diluent, PI-2-2-PDL2, PI-3-25-274 and PI-E-2-15. FIG. 108B is the zoomed in portion that is marked in FIG. 108 A.

[0145] FIG. 109 depicts a heatmap of differentially expressed genes between M2-like polarized human primary macrophages treated with diluent, PI-2-2-PDL2, PI-3-25-274 and PIE-2-15.

[0146] FIG. 110 depicts a barplot of enriched gene ontology (GO) terms of differentially expressed genes between M2-like polarized macrophages treated with diluent, PI-2-2-PDL2, PI-3-25-274 and PI-E-2-15.

[0147] FIG. Ill depicts a scatterplot of enriched GO terms of differentially expressed genes between M2-like polarized macrophages macrophages treated with diluent, PI-2-2-PDL2, PI-3-25-274 and PI-E-2-15.

[0148] FIG. 112 depicts the process for preparing polarized human monocytes with proteins of the disclosure for RNAseq and the dimensional reduction of RNAseq data of polarized macrophages from publicly accessible GEO database.

[0149] FIG. 113 depicts the dimensional reduction of RNAseq data of polarized human primary macrophages treated with diluent or proteins included in this disclosure.

[0150] FIG. 114 depicts the dimensional reduction of RNAseq data of polarized human primary macrophages treated with diluent or proteins included in this disclosure.301645057.1

[0151] FIG. 115 depicts the dimensional reduction of RNAseq data of polarized human primary macrophages treated with diluent or proteins included in this disclosure.

[0152] FIG. 116 depicts the dimensional reduction of RNAseq data of polarized human primary macrophages treated with diluent or proteins included in this disclosure.

[0153] FIG. 117 depicts the dimensional reduction of RNAseq data of polarized human primary macrophages treated with diluent or proteins included in this disclosure.

[0154] FIG. 118 depicts the dimensional reduction of RNAseq data of polarized human primary macrophages treated with diluent or proteins included in this disclosure.

[0155] FIG. 119 depicts principal component analysis (PC A) of L-012 data of polarized human primary macrophages treated with diluent or proteins included in this disclosure.

[0156] FIG. 120 A depicts pathways and networks aligned with early interception of RIF by using Ingenuity Pathway Analysis (IPA) on quantitative mRNA sequencing data from polarized human macrophages that were treated with 20 nM of PI142, PI222, or PBS for 24 hours, projected on vehicle vs. PI142.

[0157] FIG. 120B depicts pathways and networks aligned with early interception of RIF by using Ingenuity Pathway Analysis (IPA) on quantitative mRNA sequencing data from polarized human macrophages that were treated with 20 nM of PI142, PI222, or PBS for 24 hours, projected on fibrosis trend PI142<PBS<PI222.

[0158] FIG. 121 depicts a post-EBRT radiation fibrosis model.. Single dose EBRT was delivered to C57 / B16 mice and endpoint histology confirmed marked thickening of the epidermis and increased collagen deposition consistent with radiation-induced fibrosis. Qualitative analysis of midpoint responders at 4 and 5 weeks post-EBRT showed that PI- 1-4-2-treated mice exhibited visibly enhanced healing compared to diluent (PBS) treated control mice. Twelve- to fourteen-week-old C57BL / 6 mice were treated with a single 40 Gy dose of external beam radiation using an X-SMART small-animal EBRT system. Animals were monitored weekly for 6 weeks post-irradiation to assess skin changes and overall condition. At study endpoint, dorsal skin was harvested for histologic evaluation. Picrosirius Red staining revealed marked thickening of the epidermis and increased collagen deposition consistent with301645057.1radiation-induced fibrosis. Representative images demonstrate robust dermal and subepidermal collagen expansion relative to non-irradiated controls.

[0159] FIG. 122A-D depict a liver fibrosis model by using a murine Western diet (FIG.122 A) and related datapoints (FIG. 122B-D). Dietary intervention in combination with treatments included in this disclosure were evaluated by endpoint liver histology and RONS burst activity. Baseline-corrected weights were monitored for each mouse (FIG. 122B). Picrosirius red staining demonstrated a significant reduction in fibrosis following treatment with PI- 1-4-2 compared to diluent (PBS)-treated mice (FIG. 122C). H&E staining was performed, demonstrating a significant reduction in lipid droplets following treatment with PI-1-4-2 compared to diluent (PBS)-treated mice. Pseudodensity was determined by liver weight / area of the tissue (g / cm2) (FIG. 122D).

[0160] FIG. 123 depicts an HLH model using humanized mice. Neuroinflammation and survival for the humanized mouse model of HLH are depicted for mice treated with proteins included in this disclosure. . Mice (NSG-SGM3) approximately 12-weeks post humanization were treated with diluent (PBS) or PI- 1-4-2 and neuroinflammation and survival was measured post the two-week interventions. L012 imaging was performed on PBS or PI-1-4-2 treated mice throughout the course of treatment.

[0161] FIG. 124 depicts experimental layout of Genoskin ex vivo native skin model for radiation-induced inflammation and injury. Includes example experimental timeline and treatment schematic detailing collection timepoints, and endpoint tissue preparation.

[0162] FIG. 125 depicts skin appearance pre-and post-EBRT and treatment with proteins of the disclosure. White light images of the skin explants pre and post EBRT and Treatment. Boxes represent treatment groups as previously outlined in FIG. 124. Included is an example treatment schematic and example of ex- vivo skin explants prior to treatment.

[0163] FIG. 126 depicts overall skin inflammation profiles with EBRT or treatment with proteins of the disclosure, showing that the treatments did not reflect massive immunogenicity.

[0164] FIG. 127 depicts relative changes in cytokine expression, z-scored by cytokine, with EBRT or treatment with proteins of the disclosure.301645057.1

[0165] FIG. 128 depicts changes in IL-12 / IL-23p40, TARC and MCP-1 expression with EBRT or treatment with proteins of the disclosure.

[0166] FIG. 129 depicts changes in MIP-la, IL17A and GM-CSF expression with EBRT or treatment with proteins of the disclosure

[0167] FIG. 130 depicts changes in IL-6 expression with EBRT or treatment with proteins of the disclosure.

[0168] FIG. 131 depicts extracellular protein domain(s) for which proteins of interest were classified based on their known engagement in the following biological processes.

[0169] FIG. 132 depicts the therapeutic target indications by which the biological processes associated with the extracellular domains were mapped onto.

[0170] Fig. 133 is a description of an example protein of the disclosure, PI- 1-4-2-cMMP-Semi.

[0171] Fig. 134 is a SDS Page of PI-l-4-2-cMMP-Semi.

[0172] Fig. 135 shows size exclusion chromatography results of cloned and produced PI-l-4-2-cMMP-Semi.

[0173] Fig. 136 is a description of an example protein of the disclosure, PI-1-4-2-GLP1.

[0174] Fig. 134 is a SDS Page of PI-1-4-2-GLP1.

[0175] Fig. 135 shows size exclusion chromatography results of cloned and produced PI-1-4-2-GLP1.

[0176] Fig. 136 is a description of an example protein of the disclosure, PI-1-4-2-GIP.

[0177] Fig. 137 is a SDS Page of PI-1-4-2-GIP.

[0178] Fig. 135 shows size exclusion chromatography results of cloned and produced PI-1-4-2-GIP.301645057.1DESCRIPTION OF ILLUSTRATIVE EMBODIMENTSI. Definitions

[0179] As used herein the specification, “a” or “an” may mean one or more. As used herein in the claim(s), when used in conjunction with the word "comprising", the words “a” or “an” may mean one or more than one. As used herein “another” may mean at least a second or more. Still further, the terms “having,” “including,” “containing,” and “comprising” are interchangeable and one of skill in the art is cognizant that these terms are open ended terms. In specific embodiments, aspects of the disclosure may “consist essentially of’ or “consist of’ one or more sequences of the disclosure, for example. Some embodiments of the invention may consist of or consist essentially of one or more elements, method steps, and / or methods of the disclosure. It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein. The scope of the present application is not intended to be limited to the particular embodiments of the process, machine, manufacture, composition of matter, means, methods and steps described in the specification. As used herein, the terms “or” and “and / or” are utilized to describe multiple components in combination or exclusive of one another. For example, “x, y, and / or z” can refer to “x” alone, “y” alone, “z” alone, “x, y, and z,” “(x and y) or z,” “x or (y and z),” or “x or y or z.” It is specifically contemplated that x, y, or z may be specifically excluded from an embodiment.

[0180] The use of the term “or” in the claims is used to mean “and / or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and / or.” As used herein “another” may mean at least a second or more. The terms “about,” “substantially,” and “approximately” mean, in general, the stated value plus or minus 5%.

[0181] Reference throughout this specification to “one embodiment,” “an embodiment,” “a particular embodiment,” “a related embodiment,” “a certain embodiment,” “an additional embodiment,” or “a further embodiment” or combinations thereof means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the foregoing phrases in various places throughout this specification are not necessarily all301645057.1referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0182] The term “engineered” as used herein refers to an entity that is generated by the hand of man, including a cell, nucleic acid, polypeptide, vector, a combination thereof, and so forth. In at least some cases, an engineered entity is synthetic and comprises elements that are not naturally present or configured in the manner in which it is utilized in the disclosure. With respect to cells, the cells may be engineered because they express one or more nanobody genes, in which case(s) the engineering is all performed by the hand of man. With respect to an antigen receptor, the antigen receptor may be considered engineered because it comprises nanobodies.

[0183] “Treating” or treatment of a disease or condition refers to executing a protocol, which may include administering one or more drugs to a patient, in an effort to alleviate signs or symptoms of the disease. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. Alleviation can occur prior to signs or symptoms of the disease or condition appearing, as well as after their appearance. Thus, “treating” or “treatment” may include “preventing” or “prevention” of disease or undesirable condition. In addition, “treating” or “treatment” does not require complete alleviation of signs or symptoms, does not require a cure, and specifically includes protocols that have only a marginal effect on the patient.

[0184] The term “therapeutic benefit” or “therapeutically effective” as used throughout this application refers to anything that promotes or enhances the well-being of the subject with respect to the medical treatment of this condition. This includes, but is not limited to, a reduction in the frequency or severity of the signs or symptoms of a disease. For example, treatment of cancer may involve, for example, a reduction in the size of a tumor, a reduction in the invasiveness of a tumor, reduction in the growth rate of the cancer, or prevention of metastasis. Treatment of cancer may also refer to prolonging survival of a subject with cancer.

[0185] “Subject” and “patient” or “individual” refer to either a human or non-human, such as primates, mammals, and vertebrates. In particular embodiments, the subject is a human.

[0186] As used herein, a “mammal” is an appropriate subject for the method of the present invention. A mammal may be any member of the higher vertebrate class Mammalia, 301645057.1including humans; characterized by live birth, body hair, and mammary glands in the female that secrete milk for feeding the young. Additionally, mammals are characterized by their ability to maintain a constant body temperature despite changing climatic conditions. Examples of mammals are humans, cats, dogs, cows, mice, rats, horses, goats, sheep, and chimpanzees. Mammals may be referred to as “patients” or “subjects” or “individuals.”

[0187] The phrases “pharmaceutical or pharmacologically acceptable” refers to molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction when administered to an animal, such as a human, as appropriate. The preparation of a pharmaceutical composition comprising an antibody or additional active ingredient will be known to those of skill in the art in light of the present disclosure. Moreover, for animal (e.g., human) administration, it will be understood that preparations should meet sterility, pyrogenicity, general safety, and purity standards as required by FDA Office of Biological Standards.

[0188] As used herein, “pharmaceutically acceptable carrier” includes any and all aqueous solvents (e.g., water, alcoholic / aqueous solutions, saline solutions, parenteral vehicles, such as sodium chloride, Ringer's dextrose, etc.), non-aqueous solvents (e.g., propylene glycol, polyethylene glycol, vegetable oil, and injectable organic esters, such as ethyloleate), dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial or antifungal agents, anti-oxidants, chelating agents, and inert gases), isotonic agents, absorption delaying agents, salts, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, fluid and nutrient replenishers, such like materials and combinations thereof, as would be known to one of ordinary skill in the art. The pH and exact concentration of the various components in a pharmaceutical composition are adjusted according to well-known parameters.

[0189] As used herein, “immune modulation,” refers to reprogramming immunity, such as activating or inhibiting the immune system. “Homeostatic equilibrium” refers to modulating the immune system through immune modulation to return the immune system to an appropriate balance.

[0190] A “reprogramming protein,” as used herein, refers to an engineered protein that comprises one Fc domain and at least two extracellular polypeptide domains on a single chain. In embodiments, the polypeptides used to reprogram cell states are taken from the extracellular301645057.1proteins of diseased tissues or of the normal homeostatic proteins during activation and / or resolution of those tissues.

[0191] An “appended domain,” as used herein refers to an additional domain added onto an end terminus of the reprogramming protein. The appended domain can be on the N or C terminus of the reprogramming protein. In embodiments, the appended domain comprises one or more linker, appended domains, peptides, proteins, and / or small molecule.Embodiments of the Disclosure

[0192] The disclosure provides novel cellular reprogramming proteins, such as immune modulating proteins. The cellular reprogramming proteins of the disclosure can alter the transcriptional, epigenetic, signaling, metabolic or functional phenotype of cells, cell states, and tissue states. This can involve modulating more than one signaling cascade through one or more chain molecule located in the extracellular space and interacting with cells and tissues. This state then helps to either cure, intercept, or prevent a disease. This in in contrast to pure targeted inhibition or cell killing, which involve targeting single pathways or cells often for the successful interception of an acute injury or illness. In the example of immune modulating proteins, reprogramming immunity reduces the risk of infection or adverse effects seen with broad immunosuppressants. Embodiments of the disclosure also include a system comprising methods to determine which cellular reprogramming proteins return homeostatic immune equilibrium through an appropriate balance of immune activation and inhibition to the system in different immune environments.

[0193] The system can include a library of proteins comprised of combinations of two or more polypeptides and at least one Fc domain. Embodiments of the disclosure can treat, either through prevention or resolution, chronic inflammatory diseases, for example, while minimizing deleterious impacts of turning off the immune system through maximizing natural innate defenses. Through pairing the appropriate activation and inhibitory balance to the immune system or cellular subsets of immunity, embodiments enable a gentle “reset” to restore immune homeostasis. Embodiments of the disclosure include a system developed to address the debilitating effects of chronic and dysregulated inflammation, particularly as a result of anti-cancer therapy. Embodiments include single-chain biologies and a modular library design with complementary immune stimulation and suppression capabilities. The biologies can include the B7-family of immunoglobulin proteins and their supramolecular structures.301645057.1

[0194] The disclosure provides synthetic proteins with novel combinations of Fc domains and cellular reprogramming polypeptides. In embodiments, the proteins comprise at least one Fc domain and at least two extracellular polypeptides. In embodiments, the Fc domain is a human Fc domain. The Fc domain can be a wildtype domain or it can comprise an activating mutation or an inhibitory mutation. The Fc domain can be IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. In embodiments, the cellular reprogramming polypeptides are 21g-B7-H3, 4Ig-B7-H3, PD-L1 (B7-H1), PD-L2 (B7-DC), CD80 (B7-1), CD83, CD86 (B7-2), ICOS (B7-H2), B7-H4 (VTCN1), B7-H5 (VISTA), B7-H6 (NCR3LG1), B7-H7 (HHLA2), MHC-I, MHC-II, CD40, IL-18, IL-37, TNEa, IFNy, TGF-p, Cytokines, IL-15, HLA-E, CD19, CD4, HLA-B, and IL-17RB,. The cellular reprogramming polypeptides can comprise mutations that alter their immune functions, either increasing or decreasing immune activity. In specific embodiments, the synthetic protein is any one of SEQ ID NOs: 1-26, or a sequence greater than 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% similar to any one of SEQ ID NOs: 1-26. In embodiments, the synthetic protein is any one of SEQ ID Nos: 1-26 without a signaling peptide and / or His tag.

[0195] The polypeptides, proteins, or polynucleotides encoding such polypeptides or proteins of the disclosure may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 (or any derivable range therein) or more variant amino acids or nucleic acid substitutions or be at least 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% (or any derivable range therein) similar, identical, or homologous with at least, or at most 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or more contiguous amino acids or nucleotides, or any range derivable therein, of SEQ ID NOs: 1-26, respectively, with or without a signaling peptide or his tag.System and Methods for Generating Cellular reprogramming Proteins

[0196] Embodiment of the disclosure comprises systems and methods used for generating cellular reprogramming proteins. Embodiments of the disclosure include a library of engineered cellular reprogramming proteins wherein each protein comprises at least one Fc domain and at least two domains from proteins found in the extracellular space of tissues in 301645057.1either health or disease. The extracellular domains may also be referred to herein as B, C, or B / C domains. As an example one immunomodulatory subset is highly enriched in Ig containing domains and cytokines (Fig. 1). In addition to the Fc domain and at least two extracellular polypeptides, the cellular reprogramming protein can comprise one or more additional appended domains, peptides, or small molecules on either end (i.e. Fig. 70).

[0197] Embodiments utilizing a machine learning approach . In embodiments, a library of proteins comprising at least two extracellular polypeptides and at least one Fc domain is sampled. In embodiments, a known protein comprising at least two extracellular polypeptides and at least one Fc domain is sampled against the library to identify divergent and orthogonal constructs. For example, each member of the library can be represented as a vector (LV) containing the known activation or inhibitor activity or neutrality of a domain (1,-1, or 0 respectively) and a dimensionally reduced representation of the sequence and associated amino acid charge, polarity, rarity, hydrophobicity, for example (Fig. 92). In embodiments, the Fc domains can also characterized by their steady state plasma levels, and known multimerization states of their antibody isotype. A unit vector for each member of the library can be created through standardization at each element based upon the library and then normalization of its “length.” Sets of most orthogonal i.e. most different molecules are rank ordered for efficient testing in downstream assays. This is different from a small molecule library sampling whereby biological activity is sparse. Through use of domains biological activity is not sparse, but useful biological activity will be rare and likely clustered around a few key domains. In embodiments, potentially useful combinations of cellular reprogramming proteins are determined through those downstream assays.

[0198] Fig. 72 illustrates on example of a computing system which can execute a method for producing cellular reprogramming proteins. The method can include using an analytics module executed by a processor of a computer system 720, the method comprising receiving, by the analytics module from a storage device 740, a plurality of protein sequences; calculating, by the analytics module 725 executed by the processor 720, an immune modulation score for each of the protein sequences; transmitting a selected sequence from the protein sequences to a machine, such as an output device 760, wherein the selected sequence is selected based on its immune modulation score; and creating a synthetic protein with the selected sequence. A bus 750 is used to move information from one module to another. In embodiments, instead of a bus the modules within or without of the computing system 710 are301645057.1located at remote locations from each other and wired or wireless modes of data transfer are used. A user 770 can review the data output by the output device 760. In embodiments, the input / output devices 760 include keyboards, mice, monitors, printers, automated protein synthesis machines, and / or automated protein testing machines.

[0199] Once effective combinations have been identified in the library, the proteins are synthesized and tested for activity. Embodiments of testing assays include cell viability, cell differentiation, functional assays, and mRNA sequence based matching and scoring algorithms. Synthesis and testing can be performed manually or can be automated.Cancer

[0200] In embodiments, the modulating protein modulates the processes of cancer. In embodiments, the cancer is selected from the group consisting of: breast cancer; non-small cell lung cancer; small cell lung cancer; colorectal cancer; pancreatic cancer; gastric cancer; esophageal cancer; hepatocellular carcinoma; cholangiocarcinoma; ovarian cancer; endometrial cancer; cervical cancer; prostate cancer; renal cell carcinoma; bladder cancer; head and neck squamous cell carcinoma; melanoma; thyroid cancer; soft-tissue sarcoma; osteosarcoma; glioblastoma; astrocytoma; acute myeloid leukemia; acute lymphoblastic leukemia; chronic myeloid leukemia; chronic lymphocytic leukemia; Hodgkin lymphoma; non-Hodgkin lymphoma; multiple myeloma; squamous cell carcinoma; basal cell carcinoma; mesothelioma; testicular cancer; and metastatic, refractory, and recurrent cancer.

[0201] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent cancer. In embodiments, the FC domain of the cellular reprogramming protein for cancer comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides of the cellular reprogramming protein for cancer comprises ACAN, ACTH (POMC), ACTIVIN A, ACTIVIN B, ADAM10, ADAM12, ADAM17, ADAMTS1, ADAMTS4, ADAMTS5, Adenosine, ADGRE3, Adiponectin, ADIPONECTIN, ADIPOQ, ADORA2A, ADP, Adrenomedullin, AGER, AGER (RAGE), AGER / RAGE, Aggrecan, Agouti signaling protein (ASIP), Agrin, AGRIN, AGTR1, AGTR2, Albumin, ALBUMIN,301645057.1Aldosterone, ALDOSTERONE, Alpha-MSH (POMC-derived), AMH, AMHR2, AMP, Amylin, Amylin (IAPP), AMYLA°N (IAPP), Angiopoietin-like 3 (ANGPTL3), ANGIOTENSIN II, ANGIOTENSINOGEN, ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANGPTL6, ANGPTL8, ANP (NPPA), ANTLMULLERIAN HORMONE (AMH), Apelin, Apolipoprotein A-I, Apolipoprotein B, Apolipoprotein C-III, Apolipoprotein E, AR, AREG, ARTN, ATP, AVPR1A, AVPR2, BDNF, Beta-defensin 1 (hBDl), Beta-defensin 2 (hBD2), Beta-defensin 3 (hBD3), BGLAP, BGN, Biglycan, Bile acids, BMP2, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BNP (NPPB), BPIFA1, Bradykinin, Brevican, BTC, C-reactive protein, Cl, Clq, Clr, Cis, C2, C3, C3a, C3aRl, C3AR1, C4, C5, C5a, C5AR1, C5aRl / CD88, C5aR2, C6, C7, C8, C9, CALCITONIN, Calcitonin gene-related peptide (CGRP), cAMP, Carbon monoxide, Cathelicidin LL-37, CBG (SERPINA6), CCBE1, CCL1, CCL10, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL2, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CD 14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 / B7-H3 4Ig-isoform, CD36, CD44, CD80, CD86, Ceramide, cGMP, Chemerin, Cholecystokinin, CHROMOGRANIN A, Claudin-1 (CLDN1), CLEC4E, CLEC4E (MINCLE), CLEC4E / MINCLE, CLEC6A, CLEC6A (Dectin-2), CLEC6A / Dectin-2, CLEC7A, CLEC7A (Dectin-1), CLEC7A / Dectin-1, CLU, CNTF, COL11A1, COL12A1, COL14A1, COL15A1, COL18A1, COL1A1, COL1A2, COL3A1, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL5A1, COL6A1, COL6A2, COL7A1, Collagen 1, Collagen 10, Collagen 11, Collagen 12, Collagen 13, Collagen 14, Collagen 15, Collagen 16, Collagen 17, Collagen 18, Collagen 19, Collagen 2, Collagen 20, Collagen 21, Collagen 22, Collagen 23, Collagen 24, Collagen 25, Collagen 26, Collagen 27, Collagen 28, Collagen 3, Collagen 4, Collagen 5, Collagen 6, Collagen 7, Collagen 8, Collagen 9, Collagen I, Collagen II, Collagen III, Collagen IV, Collagen V, Collagen VI, Collagen VII, Collagen XII, Collagen XIV, Collagen XVII (BP180), Collagen XVIII, COMP, Contactin-1, Contactin-2, Corneodesmosin (CDSN), Corticotropin-releasing hormone (CRH), Cortisol, CORTISOL, CR1 / CD35, CR2 / CD21, CRB1, CRELD1, CRP, CSF1, CSF1R, CTSB, CTSD, CTSK, CX3CL1, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, DCN, Decorin, Defensin alpha, Defensin beta, Delta-like 1, Delta-like 4, Desmocollin 1 (DSC1), Desmocollin 3 (DSC3), Desmoglein 1 (DSG1), Desmoglein 3 (DSG3), DHEA, DHH, DKK 1, DLL4, Dopamine, Dystroglycan, E-cadherin (CDH1), EDN1, EDNRA, 301645057.1EDNRB, EFEMP1, EFEMP2, EGF, EGFL8, EGFR, Elafin (PI3), Elastin, ELN, EMILIN1, EMILIN2, Endocannabinoid 2-AG, Endocannabinoid anandamide, Endothelin-1, Endothelin-1 (EDN1), Ephrin-Al, Ephrin-A2, Ephrin-A3, Ephrin-Bl, Ephrin-B2, Epinephrine, EPO, ERBB2, ERBB3, ERBB4, EREG, ERYTHROPOIETIN (EPO), ESRI, ESR2, ESTRADIOL, F10, Fll, F12, F2, F2R / PAR1, F2RL1 / PAR2, F3, F5, F7, F8, F9, Factor B, Factor D, FAT3, FBN1, FBN3, FCAR / CD89, FCGR1A / CD64, FCGR2A / CD32, FCGR3A / CD16a, FCGR3B / CD16b, Fetuin-A, Fetuin-B, FGA, FGB, FGF1, FGF10, FGF11, FGF12, FGF13, FGF14, FGF15, FGF16, FGF17, FGF18, FGF19, FGF2, FGF20, FGF21, FGF22, FGF23, FGF3, FGF4, FGF5, FGF6, FGF7, FGF7 (KGF), FGF8, FGF9, FGFR1, FGFR2, FGFR3, FGFR4, FGG, Fibrillin-1, Fibrillin-2, Fibrinogen, Fibroblast growth factor 15 (FGF15), Fibronectin, Fibulin-2, Fibulin-5, Filaggrin-processed NMF (contextual), FLT1, FLT1 (VEGFR1), FLT4, FLT4 (VEGFR3), FN1, Follistatin, FSH, FSHR, GAL1 / LGALS1, GAL3 / LGALS3, Galectin-1 / LGALS1, Galectin-3 / LGALS3, Gastrin, GASTRIN, GCGR, GDF5, GDNF, GH, GH (GROWTH HORMONE), GHR, Ghrelin, GHRH, GHRL, GIP, GLP- 1, GLP-2, GLP1, GLP2, Glucagon, GLUCAGON, GLUT4, GNRHR, HBEGF, HCG, HEG1, Hepatic lipase, HGF, Histamine, HLA-DPB, HLA-DPB1, HLA-G, HMGB1, HSPG2, Hyaluronan, HYALURONAN, Hydrogen sulfide, IBSP, ICAM1, ICOSLG, IFNA, IFNAR1, IFNAR2, IFNB, IFNG, IFNGR1, IFNGR2, IGF1, IGF1R, IGF2, IGF2R, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, IGHG4, IGLC1, IGLC7, IGLL5, IHH, IL-1, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-17A, IL-17F, IL-18, IL-19, IL-1A, IL-1B, IL- 2, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-3, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL10, IL10RA, IL10RB, IL12RB1, IL12RB2, IL13, IL13RA1, IL15, IL17A, IL17RA, IL17RC, IL18R1, IL18RAP, ILIA, IL1B, IL1R1, IL1R2, IL1RL1 (ST2), IL22, IL22RA1, IL25, IL33, IL33R (ST2 / IL1RL1), IL6, IL6R, IL7, IL8, INHIBIN A, INHIBIN B, INS, INSR, Insulin, Insulin-like growth factor 1 (IGF1), INSULIN-LIKE GROWTH FACTOR 1 (IGF1), INSULIN-LIKE GROWTH FACTOR 2 (IGF2), Integrin alpha3 (ITGA3), Integrin alpha6 (ITGA6), Integrin betal (ITGB1), Integrin beta4 (ITGB4), Integrin a7, Integrin piD, Irisin, ITGA1, ITGA2, ITGA3, TTGA4, ITGA5, ITGA6, ITGA9, ITGAE, ITGAM / CDllb, TTGAV, ITGAX / CDllc, ITGB1, ITGB2, ITGB2 / CD18, ITGB3, ITGB4, ITGB5, ITGB6, ITGB7, ITGB8, IZUMO1, Jaggedl, Jagged2, JUNO, Kallidin, Kallikrein KLK14, Kallikrein KLK5, Kallikrein KLK7, KDR, KDR (VEGFR2), KISS1R, KISSPEPTIN, KITLG (SCF), KLB, KLOTHO, L1CAM, Lactoferrin, LAMA1, LAMA2, LAMA3, LAMA4, LAMA5, LAMB1, LAMB2, LAMC1, Laminin, LAMININ, Laminin- 111, Laminin-332, Laminin-511, Laminin-521, LBP, LDLR, 301645057.1LECT2, LEKTI (SPINK5), LEP, LEPR, Leptin, LEPTIN, Leukotriene B4, Leukotriene C4, Leukotriene D4, Leukotriene E4, LGALS1, LGALS3, LH, LHR, LIE, Lipocalin-2, Lipoprotein lipase, Lipoxin A4, Lipoxin B4, LPS-binding protein, LRP8, LTA, LTB, LTBP1, LTBP2, LTBP4, LUB RICIN, Lumican, LY86 / MD-1, LY96, LY96 (MD-2), LY96 / MD-2, Lysophosphatidic acid, Lysozyme, LYVE1, MADCAM1, Mannose-binding lectin, Maresin 1, MASP2, MATN1, MATN3, Melatonin, MELATONIN, MMP1, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP18, MMP19, MMP2, MMP20, MMP21, MMP22, MMP23, MMP24, MMP25, MMP26, MMP27, MMP28, MMP3, MMP4, MMP5, MMP6, MMP7, MMP8, MMP9, Motilin, MOTILIN, MSR1 / SR-A1, MUC1, MUC16, MUC2, MUC4, MUC5AC, MUC5B, Myostatin (GDE8), MYOSTATIN / GDE8, N-cadherin (CDH2), NCAM1, NELLI, NELL2, Netrin-1, Netrin-3, Netrin-4, Neurexin-1, Neurexin-2, Neurexin-3, Neurocan, Neuroligin-1, Neuroligin-2, Neuroligin-3, Neuropeptide Y, NGE, NIDI, NID2, Nidogen, Nidogen-1, Nidogen-2, Nitric oxide, Nitric oxide synthase (eNOS), NODI, NOD2, Norepinephrine, NOTCH1, NOTCH2NLB, NOTCH3, NPR 1, NPR 2, NPR 3, NR3C1 (GLUCOCORTICOID RECEPTOR), NR3C2 (MINERALOCORTICOID RECEPTOR), NrCAM, NRTN, NT-3, NT-4, Occludin (OCLN), Omentin, OPG, Osteocalcin, Osteopontin, OXTR, Oxyntomodulin, OXytocin, OXYTOCIN, P2RX7, PALI, Pancreatic polypeptide, Parathyroid hormone, PDCD1LG2, PDCD1LG2 (PD-L2), PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFC, PDGFD, PDGFRA, PDGFRB, PDPN (Podoplanin), PECAM1, Pentraxins PTX3, Periostin, Perlecan, Peroxynitrite, PGR, Plasminogen, Platelet-activating factor (PAP), PLG, POSTN, PRG4, PRLR, PROGESTERONE, PROLACTIN, Properdin, PROS1, Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), Prostaglandin F2a (PGF2a), Protectin DI, PSPN, PTH, PTH1R, PTHRP, PTX3, PYY, RANKL, RBP4, Reactive oxygen species, Reelin, REG3A, REG3G, RELAXIN, RELN, RENIN, Resistin, Resolvin DI, Resolvin D2, Resolvin El, RETINOL-BINDING PROTEIN 4, RP105 / TLR5L, RSPO1, RSPO2, RSPO3, RSPO4, S100A1, S100A5, S100A6, S100A7, S100A7 (Psoriasin), S100A8, S100A9, SCARB1, SCGB1A1, Sclerostin, SCUBE1, Secretin, SECRETIN, Secretory IgA, SELE, SELE (E- selectin), Selenoprotein P, SELP, SELP (P- selectin), Semaphorin3A, Semaphorin3F, Semaphorin4D, Serotonin, SERPINE1, Serum amyloid A, SFTPA1, SFTPA2, SFTPB, SFTPC, SFTPD, SHH, SIGLEC1, SIGLEC10, SIGLEC14, SIGLEC7, SIGLEC9, SIRT1, Slitl, Slit2, Slit3, SLPI, Somatostatin, SOMATOSTATIN, SOST, SPARC, Sphingosine- 1-phosphate, SPON1, SPP1, SSTR2, Substance P, Tenascin-C, Tenascin-R, Tenascin-X, TESTOSTERONE, TGF-beta, TGF-betal, TGF-betal (TGFB1), TGF-beta2, TGF-beta2 (TGFB2), TGF-beta3, TGF-beta3 (TGFB3), TGFA, TGFB1, TGFB2, TGFB3, TGFBR1, 301645057.1TGFBR2, THBS1, THBS2, THBS3, Thrombin, Thrombospondin- 1, Thrombospondin-2, Thromboxane A2, THYROGLOBULIN, THYROID PEROXIDASE, Thyroxine (T4), THYROXINE (T4), TIE2, TIMP1, TIMP2, TIMP3, TIMP4, TLL1, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TNC, TNF, TNFRSF11A (RANK), TNFRSF11B (OPG), TNFRSF1A, TNFRSF1B, TNFSF10, TNFSF11, TNFSF11 (RANKL), TNFSF12, TNFSF13, TNFSF14, TNFSF15, TNFSF4, TNFSF8, TNFSF9, TPO, Transferrin, TRANSTHYRETIN, TREM1, TREM2, Triiodothyronine (T3), TRIIODOTHYRONINE (T3), TSHR, TSLP, TSLP receptor (TSLPR / CRLF2), UDP, UMOD, uPA / PLAU, UTP, Vasoactive intestinal peptide, VASOPRESSIN (A VP), VCAM1, VCAN, VDR, VEGFA, VEGFB, VEGFC, VEGFD, VEGFR2 (KDR), VEGFR3 (FLT4), Versican, Visfatin, VITAMIN D (CALCITRIOL), VITAMIN D BINDING PROTEIN (GC), Vitronectin, VLDLR, VTCN1, VTCN1 (B7-H4), VTCN1 / B7-H4, VWCE, VWF, WNT1, WNT10A, WNT10B, WNT11, WNT16, WNT2, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, ZP3, ZP4, a-Sarcoglycan, P-Sarcoglycan, y-Sarcoglycan, and / or 6-Sarcoglycan. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein additionally comprises one or more appended domains. In embodiments the appended protein is flagellin, p28, or derivatives.Fibrosis

[0202] In embodiments, the cellular reprogramming protein modulates the immune processes of cancer. In embodiments, the fibrosis is radiation induced fibrosis, autoimmune fibrosis, diet induced fibrosis, surgical adhesions, ischemia reperfusion induced fibrosis, chemical toxicant or contrast agent induced fibrosis, chemo therapy induced liver and kidney fibrosis.

[0203] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent fibrosis. In embodiments, the FC domain of the cellular reprogramming protein for fibrosis comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprises ACAN, ADAM10, AD AMU, ADAMTS1, ADAMTS4, ADAMTS5, Adenosine, ADGRE3, ADIPOQ, ADORA2A, ADP, AGER, AGER (RAGE), AGER / RAGE, 301645057.1Agouti signaling protein (ASIP), Agrin, AGRIN, AGTR1, AGTR2, ALDOSTERONE, Alpha-MSH (POMC-derived), AMP, ANGIOTENSIN II, ANGIOTENSINOGEN, ANGPT1, ANGPT2, ANP (NPPA), AREG, ATP, AVPR1A, AVPR2, Beta-defensin 1 (hBDl), Beta-defensin 2 (hBD2), Beta-defensin 3 (hBD3), BGLAP, BGN, Biglycan, BMP2, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BNP (NPPB), BPIFA1, Bradykinin, BTC, C-reactive protein, Cl, Clq, Clr, Cis, C2, C3, C3a, C3aRl, C3AR1, C4, C5, C5a, C5AR1, C5aRl / CD88, C5aR2, C6, C7, C8, C9, CALCITONIN, Calcitonin gene-related peptide (CGRP), cAMP, Carbon monoxide, Cathelicidin LL-37, CCBE1, CCL1, CCL10, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL2, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CD14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform, CD36, CD44, CD80, CD86, Ceramide, cGMP, Cholecystokinin, Claudin-1 (CLDN1), CLEC4E, CLEC4E (MINCLE), CLEC4E / MINCLE, CLEC6A, CLEC6A (Dectin-2), CLEC6A / Dectin-2, CLEC7A, CLEC7A (Dectin-1), CLEC7A / Dectin-1, COL11A1, COL12A1, COL14A1, COL15A1, COL18A1, COL1A1, COL1A2, COL3A1, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL5A1, COL6A1, COL6A2, COL7A1, Collagen 1, Collagen 10, Collagen 11, Collagen 12, Collagen 13, Collagen 14, Collagen 15, Collagen 16, Collagen 17, Collagen 18, Collagen 19, Collagen 2, Collagen 20, Collagen 21, Collagen 22, Collagen 23, Collagen 24, Collagen 25, Collagen 26, Collagen 27, Collagen 28, Collagen 3, Collagen 4, Collagen 5, Collagen 6, Collagen 7, Collagen 8, Collagen 9, Collagen I, Collagen II, Collagen III, Collagen IV, Collagen V, Collagen VI, Collagen VII, Collagen XII, Collagen XIV, Collagen XVII (BP180), Collagen XVIII, COMP, Comeodesmosin (CDSN), Corticotropinreleasing hormone (CRH), CR1 / CD35, CR2 / CD21, CRELD1, CRP, CSF1, CSF1R, CTSK, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, DCN, Decorin, Defensin alpha, Defensin beta, Delta-like 1, Delta-like 4, Desmocollin 1 (DSC1), Desmocollin 3 (DSC3), Desmoglein 1 (DSG1), Desmoglein 3 (DSG3), DHH, DKK 1, DLL4, Dopamine, E-cadherin (CDH1), EDN1, EDNRA, EDNRB, EFEMP2, EGF, EGFR, Elafin (PI3), Elastin, ELN, EMILIN 1, EMILIN2, Endocannabinoid 2- AG, Endocannabinoid anandamide, Endothelin-1, Endothelin-1 (EDN1), Epinephrine, ERBB2, ERBB3, ERBB4, EREG, ERYTHROPOIETIN (EPO), F10, Fll, F12, F2, F2R / PAR1, F2RL1 / PAR2, F3, F5, F7, F8, F9, Factor B, Factor D, FBN1, FBN3, FCAR / CD89, FCGR1A / CD64, FCGR2A / CD32, FCGR3A / CD16a, FCGR3B / CD16b, FGA, 301645057.1FGB, FGF1, FGF10, FGF11, FGF12, FGF13, FGF14, FGF15, FGF16, FGF17, FGF18, FGF19, FGF2, FGF20, FGF21, FGF22, FGF23, FGF3, FGF4, FGF5, FGF6, FGF7, FGF7 (KGF), FGF8, FGF9, FGFR1, FGFR2, FGFR3, FGFR4, FGG, Fibrillin-1, Fibrillin-2, Fibrinogen, Fibronectin, Fibulin-2, Fibulin-5, Filaggrin-processed NMF (contextual), FLT1, FLT1 (VEGFR1), FLT4, FLT4 (VEGFR3), FN1, GAL1 / LGALS1, GAL3 / LGALS3, Gastrin, GDF5, GH, Ghrelin, GHRL, GIP, GLP-1, GLP-2, HBEGF, HEG1, Histamine, HLA-DPB, HLA-DPB 1, HMGB 1, HSPG2, HYALURONAN, Hydrogen sulfide, IBSP, ICAM1, ICOSLG, IFNA, IFNAR1, IFNAR2, IFNB, IFNG, IFNGR1, IFNGR2, IGF1, IGF1R, IGF2, IGHG4, IGLC1, IGLC7, IGLL5, IHH, IL-1, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-17A, IL-17F, IL-18, IL-19, IL-1A, IL-1B, IL-2, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-3, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL10, IL10RA, IL10RB, IL12RB1, IL12RB2, IL13, IL13RA1, IL15, IL17A, IL17RA, IL17RC, IL18R1, IL18RAP, ILIA, IL1B, IL1R1, IL1R2, IL1RL1 (ST2), IL22, IL22RA1, IL25, IL33, IL33R (ST2 / IL1RL1), IL6, IL6R, IL7, IL8, INS, Integrin alpha3 (ITGA3), Integrin alpha6 (ITGA6), Integrin betal (ITGB1), Integrin beta4 (ITGB4), ITGA1, ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGA9, ITGAE, ITGAM / CDllb, ITGAV, ITGAX / CDllc, ITGB1, ITGB2, ITGB2 / CD18, ITGB3, ITGB4, ITGB5, ITGB6, ITGB7, ITGB8, Jaggedl, Jagged2, Kallidin, Kallikrein KLK14, Kallikrein KLK5, Kallikrein KLK7, KDR, KDR (VEGFR2), KITLG (SCF), KLB, KLOTHO, Lactoferrin, LAMA1, LAMA2, LAMA3, LAMA4, LAMA5, LAMB1, LAMB2, LAMC1, Laminin, Laminin-Ill, Laminin-332, Laminin-511, Laminin-521, LBP, LEKTI (SPINK5), LEP, Leukotriene B4, Leukotriene C4, Leukotriene D4, Leukotriene E4, LIF, Lipoxin A4, Lipoxin B4, LPS-binding protein, LTA, LTB, LTBP1, LTBP2, LTBP4, LUBRICIN, Lumican, LY86 / MD-1, LY96, LY96 (MD-2), LY96 / MD-2, Lysophosphatidic acid, Lysozyme, LYVE1, MADCAM1, Mannose-binding lectin, Maresin 1, MASP2, MATN1, MATN3, Melatonin, MMP1, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP18, MMP19, MMP2, MMP20, MMP21, MMP22, MMP23, MMP24, MMP25, MMP26, MMP27, MMP28, MMP3, MMP4, MMP5, MMP6, MMP7, MMP8, MMP9, Motilin, MSR1 / SR-A1, MUC1, MUC16, MUC2, MUC4, MUC5AC, MUC5B, N-cadherin (CDH2), NELLI, Neuropeptide Y, NIDI, NID2, Nidogen, Nidogen-1, Nidogen-2, Nitric oxide, Nitric oxide synthase (eNOS), NODI, NOD2, Norepinephrine, NOTCH3, NPR 1, NPR2, NPR 3, Occludin (OCLN), Osteopontin, P2RX7, PALI, PDCD1LG2, PDCD1LG2 (PD-L2), PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFC, PDGFD, PDGFRA, PDGFRB, PDPN (Podoplanin), PECAM1, Pentraxins PTX3, Periostin, Perlecan, Peroxynitrite, Plasminogen, Platelet- activating factor (PAF), PLG, 301645057.1POSTN, PRG4, Properdin, PROS1, Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), Prostaglandin F2a (PGF2a), Protectin DI, PTH, PTH1R, PTX3, PYY, Reactive oxygen species, REG3A, REG3G, RELN, RENIN, Resolvin DI, Resolvin D2, Resolvin El, RP105 / TLR5L, RSPO1, RSPO2, RSPO3, RSPO4, S100A1, S100A6, S100A7, S100A7 (Psoriasin), S100A8, S100A9, SCGB1A1, SCUBE1, Secretin, Secretory IgA, SELE, SELE (E-selectin), SELP, SELP (P-selectin), Serotonin, SERPINE1, Serum amyloid A, SFTPA1, SFTPA2, SFTPB, SFTPC, SFTPD, SHH, SIGLEC1, SIGLEC10, SIGLEC14, SIGLEC7, SIGLEC9, SLPI, Somatostatin, SOST, SPARC, Sphingosine- 1 -phosphate, SPON1, SPP1, Substance P, Tenascin-C, Tenascin-X, TGF-betal, TGF-betal (TGFB1), TGF-beta2, TGF-beta2 (TGFB2), TGF-beta3, TGF-beta3 (TGFB3), TGFA, TGFB 1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, THBS3, Thrombin, Thrombospondin- 1, Thrombospondin-2, Thromboxane A2, TIE2, TIMP1, TIMP2, TIMP3, TIMP4, TLL1, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TNC, TNF, TNFRSF11A (RANK), TNFRSF11B (OPG), TNFRSF1A, TNFRSF1B, TNFSF10, TNFSF11, TNFSF11 (RANKL), TNFSF12, TNFSF13, TNFSF14, TNFSF15, TNFSF4, TNFSF8, TNFSF9, TREM1, TREM2, TSLP, TSLP receptor (TSLPR / CRLF2), UDP, UMOD, UTP, Vasoactive intestinal peptide, VASOPRESSIN (A VP), VCAM1, VCAN, VEGFA, VEGFB, VEGFC, VEGFD, VEGFR2 (KDR), VEGFR3 (FLT4), Versican, VITAMIN D (CALCITRIOL), Vitronectin, VTCN1, VTCN1 (B7-H4), VTCN1 / B7-H4, VWCE, VWF, WNT1, WNT10A, WNT10B, WNT11, WNT16, WNT2, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, and / or WNT9B. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for fibrosis additionally comprises one or more appended domains. In one embodiment the appended domain is a Ac-SDKP.N eurodegeneration

[0204] In embodiments, the cellular reprogramming protein modulates the immune processes of neurodegeneration. In embodiments, the neurodegeneration is Alzheimer’s disease & related dementias, Parkinsonian disorders, Motor neuron & neuromuscular neurodegeneration, demyelinating and immune-mediated neurodegeneration, metabolic and lysosomal neurodegenerative diseases, prion-related or rapidly progressive neurodegenerative disorders, epilepsy-associated neurodegeneration, peripheral neurodegenerative neuropathies, movement disorders such as Wilson disease or Huntington’s disease, infectious or post-infectious neurodegeneration.301645057.1

[0205] In specific embodiments, the neurodegeneration is Alzheimer’s disease (mixed pathology), Primary age-related tauopathy (PART), Progressive supranuclear palsy (PSP), Corticobasal degeneration (CBD), Argyrophilic grain disease, Chronic traumatic encephalopathy (CTE), FTLD-tau (MAPT mutations and sporadic forms), Parkinson’s disease (PD), Dementia with Lewy bodies (DLB), Multiple system atrophy (MSA) - parkinsonian & cerebellar subtypes, Pure autonomic failure (PAF), Frontotemporal dementia - TDP-43 variants (including C9orf72), ALS (amyotrophic lateral sclerosis) - TDP-43 dominant subtype, Limbic-predominant age-related TDP-43 encephalopathy (LATE), FUS-related FTD, Prion diseases (CJD, vCJD, FFI, GSS), Huntington’s disease (polyglutamine expansion), Spinocerebellar ataxias (SCA1-SCA48), DRPLA (dentatorubral-pallidoluysian atrophy), Neuroacanthocytosis syndromes (ChAc, McLeod), ALS (amyotrophic lateral sclerosis), Primary lateral sclerosis (PLS), Spinal muscular atrophy (SMA) - types 1-4, Kennedy’s disease (SBMA), Hereditary spastic paraplegias (>80 genetic types), Alzheimer’s disease spectrum, Alzheimer’s disease (early- and late-onset), Mixed dementia (AD + vascular + Lewy body), Behavioral- variant FTD, Semantic variant PPA, Nonfluent / agrammatic PPA, FTD-MAPT, FTD-TDP-43, FTD-FUS, C. Vascular neurodegenerative conditions, Vascular dementia, CADASIL (NOTCH3), CARASIL, Cerebral amyloid angiopathy-related dementia, Juvenile parkinsonism (various genetic forms), Atypical Parkinsonian Syndromes, Progressive supranuclear palsy, Corticobasal syndrome, Multiple system atrophy - parkinsonian type, Dystonia (genetic and primary forms), Ataxias (hereditary and idiopathic), Wilson disease (copper metabolism disorder with neurodegeneration) tic PPA, Vascular dementia, Cerebral amyloid angiopathy-related dementia, Inherited Peripheral Neuropathies, Charcot-Marie-Tooth disease (CMT1-CMTX, many subtypes), Hereditary sensory and autonomic neuropathies (HSAN), Transthyretin amyloidosis (familial & wild-type ATTR), Giant axonal neuropathy, Metachromatic leukodystrophy (late-onset variants), Gaucher disease type 3, Niemann-Pick type C, Krabbe disease (late-onset), Fabry disease (neuropathy + cerebrovascular decline), Pompe disease (late-onset), GM1 gangliosidosis, GM2 / Tay-Sachs late-onset, Mucopolysaccharidoses (MPS I, II, III, IV, VI, VII — neurologic subtypes), Adrenoleukodystrophy (adult cerebral ALD & AMN), VII. Leukodystrophies (Adult & Childhood Forms), Adult-onset leukodystrophy with axonal spheroids (ALSP), Alexander disease, Canavan disease, Pelizaeus-Merzbacher disease, Vanishing white matter disease, POLR3-related leukodystrophy, AARS2 leukodystrophy, Retinitis pigmentosa, Stargardt disease, Leber hereditary optic neuropathy (LHON), Cone-rod dystrophies, Glaucoma (progressive optic nerve neurodegeneration), HIV-associated neurocognitive disorder, 301645057.1HTLV-1 -associated myelopathy, Neurosyphilis, Multiple sclerosis (MS), Neuromyelitis optica (NMOSD), MOG-associated disease, or Chronic inflammatory demyelinating polyneuropathy (CIDP).

[0206] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent neurodegeneration. In embodiments, the FC domain of the cellular reprogramming protein for neurodegeneration comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprises Neurodegeneration ACTH (POMC), ADAM10, ADAM17, ADAMTS1, ADAMTS4, Adenosine, ADGRE3, Adiponectin, ADIPONECTIN, ADIPOQ, ADORA2A, ADP, Adrenomedullin, AGER, AGER / RAGE, Aggrecan, Agrin, AGTR1, AGTR2, Albumin, ALBUMIN, Aldosterone, ALDOSTERONE, AMH, AMP, Amylin, Amylin (IAPP), AMYLA°N (IAPP), Angiopoietin-like 3 (ANGPTL3), ANGIOTENSIN II, ANGIOTENSINOGEN, ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANGPTL6, ANGPTL8, ANP (NPPA), Apelin, Apolipoprotein A-I, Apolipoprotein B, Apolipoprotein C-III, Apolipoprotein E, AR, ARTN, ATP, AVPR1A, AVPR2, BDNF, BGN, Biglycan, Bile acids, BMP2, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BNP (NPPB), Bradykinin, Brevican, C-reactive protein, Cl, Clq, Clr, Cis, C2, C3, C3a, C3aRl, C3AR1, C4, C5, C5a, C5AR1, C5aRl / CD88, C5aR2, C6, C7, C8, C9, CALCITONIN, Calcitonin gene-related peptide (CGRP), cAMP, Carbon monoxide, Cathelicidin LL-37, CBG (SERPINA6), CCL19, CCL2, CCL20, CCL21, CCL3, CCL4, CCL5, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CD14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform, CD36, CD80, CD86, Ceramide, cGMP, Chemerin, Cholecystokinin, CHROMOGRANIN A, CLEC4E / MINCLE, CLEC6A / Dectin-2, CLEC7A / Dectin-1, CLU, CNTF, COL18A1, COL1A1, COL1A2, COL3A1, COL4A1, COL4A2, COL5A1, COL6A1, COL6A2, COL7A1, Collagen I, Collagen II, Collagen III, Collagen IV, Collagen V, Collagen VI, Contactin- 1, Contactin-2, Corticotropin-releasing hormone (CRH), Cortisol, CORTISOL, CR1 / CD35, CR2 / CD21, CRB1, CRELD1, CRP, CX3CL1, CXCL1, CXCL10, CXCL11, CXCL12, CXCL14, CXCL2, CXCL3, CXCL8, CXCL9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, DCN, Decorin, Defensin alpha, Defensin beta, Delta-like 1, Delta-like 4, DHEA, DHH, DKK 1, DLL4, Dopamine, EDN1, EDNRA, EDNRB, EFEMP1, EGFL8,301645057.1Endocannabinoid 2-AG, Endocannabinoid anandamide, Endothelin-1, Ephrin-Al, Ephrin-A2, Ephrin-A3, Ephrin-Bl, Ephrin-B2, Epinephrine, EPO, ESRI, ESR2, F2R / PAR1, F2RL1 / PAR2, Factor B, Factor D, FAT3, FCAR / CD89, FCGR1A / CD64, FCGR2A / CD32, FCGR3A / CD16a, FCGR3B / CD16b, Fetuin-A, Fetuin-B, FGA, FGB, FGF1, FGF10, FGF18, FGF19, FGF2, FGF20, FGF21, FGF23, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, FGFR1, FGFR2, FGFR4, FGG, Fibrinogen, Fibroblast growth factor 15 (FGF15), Fibronectin, FET1, FET4, FN1, Follistatin, FSH, FSHR, GAE1 / EGAES1, GAE3 / EGAES3, Gastrin, GASTRIN, GCGR, GDNF, GH (GROWTH HORMONE), GHR, Ghrelin, GHRH, GHRE, GIP, GEP-1, GEP-2, GEP1, GEP2, Glucagon, GEUCAGON, GEUT4, HCG, HEG1, Hepatic lipase, HGF, Histamine, HEA-DPB, HEA-DPB1, HMGB1, HSPG2, Hyaluronan, Hydrogen sulfide, ICAM1, ICOSEG, IFNA, IFNAR1, IFNAR2, IFNB, IFNG, IFNGR1, IFNGR2, IGF1, IGF1R, IGF2, IGF2R, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, IGHG4, IGEC1, IGEC7, IGEE5, IHH, IE-10, IE-11, IE-12, IE-17A, IE-18, IE-1A, IE-1B, IE-22, IL-6, IL-8, IL10, IL10RA, IL10RB, IL12RB1, IL12RB2, IL17A, IL17RA, IL17RC, IL18R1, IL18RAP, ILIA, IL1B, IL1R1, IL1R2, IL22, IL22RA1, IL6, IL6R, INS, INSR, Insulin, Insulin-like growth factor 1 (IGF1), INSULIN-LIKE GROWTH FACTOR 1 (IGF1), INSULIN-LIKE GROWTH FACTOR 2 (IGF2), Irisin, ITGA1, ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGAM / CDllb, ITGAV, ITGAX / CDllc, ITGB1, ITGB2, ITGB2 / CD18, ITGB3, ITGB4, ITGB5, Jaggedl, Jagged2, Kallidin, KDR, KLB, L1CAM, Lactoferrin, LAMA1, LAMA4, LAMA5, LAMB1, LAMB 2, LAMC1, Laminin, LAMININ, LBP, LDLR, LECT2, LEP, LEPR, Leptin, LEPTIN, Leukotriene B4, Leukotriene C4, Leukotriene D4, Leukotriene E4, LH, LHR, LIF, Lipocalin-2, Lipoprotein lipase, Lipoxin A4, Lipoxin B4, LPS-binding protein, LRP8, LTBP1, Lumican, LY86 / MD-1, LY96, LY96 / MD-2, Lysophosphatidic acid, Lysozyme, Mannose-binding lectin, Maresin 1, MASP2, Melatonin, MELATONIN, MMP1, MMP10, MMP11, MMP12, MMP13, MMP14, MMP16, MMP2, MMP3, MMP4, MMP5, MMP6, MMP7, MMP8, MMP9, Motilin, MOTILIN, MSR1 / SR-A1, MUC1, MUC2, MUC5AC, Myostatin (GDF8), NCAM1, NELL2, Netrin-1, Netrin-3, Netrin-4, Neurexin-1, Neurexin-2, Neurexin-3, Neurocan, Neuroligin-1, Neuroligin-2, Neuroligin-3, Neuropeptide Y, NGF, NIDI, NID2, Nidogen, Nitric oxide, Nitric oxide synthase (eNOS), Norepinephrine, NOTCH1, NOTCH2NLB, NOTCH3, NPR 1, NPR 2, NPR 3, NR3C1 (GLUCOCORTICOID RECEPTOR), NR3C2 (MINERALOCORTICOID RECEPTOR), NrCAM, NRTN, NT-3, NT-4, Omentin, OPG, Osteocalcin, OXTR, Oxyntomodulin, OXYTOCIN, P2RX7, PALI, Pancreatic polypeptide, Parathyroid hormone, PDCD1LG2, PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFRA, PDGFRB, PECAM1, Pentraxins PTX3, Perlecan, Peroxynitrite, 301645057.1Plasminogen, Platelet- activating factor (PAF), PLG, POSTN, PRLR, PROLACTIN, Properdin, PROS1, Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), Prostaglandin F2a (PGF2a), Protectin DI, PSPN, PTH, PTH1R, PTHRP, PTX3, PYY, RANKL, RBP4, Reactive oxygen species, Reelin, RENIN, Resistin, Resolvin DI, Resolvin D2, Resolvin El, RETINOL-BINDING PROTEIN 4, RP105 / TLR5L, RSPO1, RSPO2, RSPO3, RSPO4, S100A1, S100A5, S100A6, S100A7, S100A8, S100A9, SCARB1, Sclerostin, SCUBE1, Secretin, SECRETIN, Secretory IgA, SELE, Selenoprotein P, SELP, Semaphorin3A, Semaphorin3F, Semaphorin4D, Serotonin, SERPINE1, Serum amyloid A, SHH, SIGLEC1, SIGLEC10, SIGLEC14, SIGLEC7, SIGLEC9, SIRT1, Slitl, Slit2, Slit3, Somatostatin, SOMATOSTATIN, SPARC, Sphingosine- 1 -phosphate, SPP1, SSTR2, Substance P, Tenascin-C, Tenascin-R, TESTOSTERONE, TGF-beta, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, THBS3, Thrombin, Thromboxane A2, THYROGLOBULIN, THYROID PEROXIDASE, Thyroxine (T4), THYROXINE (T4), TLL1, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TNC, TNF, TNFRSF1A, TNFRSF1B, TPO, Transferrin, TRANSTHYRETIN, TREM1, TREM2, Triiodothyronine (T3), TRIIODOTHYRONINE (T3), TSHR, UDP, UTP, Vasoactive intestinal peptide, VASOPRESSIN (A VP), VCAM1, VCAN, VDR, VEGFA, VEGFB, VEGFC, VEGFD, Versican, Visfatin, VITAMIN D (CALCITRIOL), VITAMIN D BINDING PROTEIN (GC), Vitronectin, VLDLR, VTCN1 / B7-H4, VWF, WNT1, WNT10A, WNT10B, WNT11, WNT16, WNT2, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, and / or WNT9B. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for neurodegeneration additionally comprises one or more appended domains. In an embodiment, the appended domain is humanin.1. Deconditioning

[0207] In embodiments, the cellular reprogramming protein modulates the immune processes of deconditioning. In embodiments, the deconditioning is skeletal muscle deconditioning disorders, cardiovascular deconditioning, metabolic and endocrine deconditioning, neuromuscular deconditioning, respiratory and pulmonary deconditioning, systemic disease-associated deconditioning, psychiatric and behavioral conditions leading to deconditioning and special populations / context-specific deconditioning such as geriatric syndrome and spaceflight.301645057.1

[0208] In specific embodiments the deconditioning is Sarcopenia (age-related muscle loss), Cachexia (cancer-related or chronic illness-associated) , Frailty syndrome (multi-system decline with prominent deconditioning), Protein-energy malnutrition-related muscle wasting, Chronic starvation or anorexia-related muscle loss, B. Disuse-Related Muscle Deconditioning, Prolonged immobilization (casting, bedrest, ICU stay, for example), Post-ICU syndrome (PICS), Hospital-associated deconditioning, Sedentary lifestyle-associated myopenia, Orthostatic & Autonomic Forms, Postural orthostatic tachycardia syndrome (POTS), Orthostatic intolerance syndromes, Neurogenic orthostatic hypotension (NOH) with secondary deconditioning, Hypokinetic Cardiovascular Syndromes, Cardiac atrophy from prolonged inactivity, Astronaut cardiovascular deconditioning (micro gravity-induced), Cardiopulmonary deconditioning after long-term illness, III. Metabolic & Endocrine Deconditioning, Movement-Restriction-Driven Metabolic Decline, Insulin resistance due to inactivity, Metabolic inflexibility (reduced fat oxidation capacity), Inactivity-related obesity and adipose remodeling, Endocrine-linked Muscle Deconditioning, Glucocorticoid-induced myopathy (chronic steroid exposure), Thyroid-related, deconditioning (hypothyroid myopathy), Peripheral Nerve-Associated Disuse Syndromes, Peripheral neuropathy-associated disuse atrophy, Entrapment neuropathies with secondary muscle wasting, Chronic Pain-Related Deconditioning, Fibromyalgia-associated deconditioning, Chronic low back pain with movement avoidance and subsequent muscle decline, Pulmonary Muscle Weakness, Chronic obstructive pulmonary disease (COPD) deconditioning, Interstitial lung disease (ILD)-associated deconditioning, Diaphragmatic disuse atrophy due to prolonged mechanical ventilation, Post-Illness Functional Decline, Post-COVID-19 chronic post-viral deconditioning, Post-pneumonia or post-ARDS respiratory deconditioning, Chronic Organ Failure, Chronic heart failure-associated muscle wasting (cardiac cachexia), Chronic kidney disease-related muscle atrophy, Advanced liver disease with sarcopenia (cirrhosis-associated myopathy), Chronic inflammatory disease-associated deconditioning, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, Chronic Infections, HIV-associated wasting, Tuberculosis-associated deconditioning, Major depressive disorder with psychomotor slowing / inactivity, Severe anxiety or PTSD leading to activity avoidance, Substance-use-related physical decline, Geriatric Syndromes, Geriatric frailty (multisystem deconditioning), Mobility impairment-associated deconditioning, Spaceflight / Extreme Environments, Microgravity-induced musculoskeletal & cardiovascular deconditioning, and / or Prolonged confinement (e.g., submariners, isolation).301645057.1

[0209] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent deconditioning. In embodiments, the FC domain of the cellular reprogramming protein for deconditioning comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprises ACAN, ACTH (POMC), ADAMIO, ADAM12, ADAM17, ADAMTS1, ADAMTS4, Adiponectin, ADIPONECTIN, ADIPOQ, Adrenomedullin, AGER, Agrin, AGTR1, AGTR2, Albumin, ALBUMIN, Aldosterone, ALDOSTERONE, AMH, Amylin, Amylin (IAPP), AMYLA°N (IAPP), Angiopoietin-like 3 (ANGPTL3), ANGIOTENSIN II, ANGIOTENSINOGEN, ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANGPTL6, ANGPTL8, ANP (NPPA), Apelin, Apolipoprotein A-I, Apolipoprotein B, Apolipoprotein C-III, Apolipoprotein E, AR, AVPR1A, AVPR2, BDNF, BGLAP, BGN, Bile acids, BMP2, BMP4, BMP6, BMP7, BNP (NPPB), C3, C3AR1, C5, C5AR1, CALCITONIN, CBG (SERPINA6), CCL19, CCL2, CCL21, CCL5, CD14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform, CD36, CD80, CD86, Chemerin, Cholecystokinin, CHROMOGRANIN A, COL11A1, COL12A1, COL14A1, COL15A1, COL18A1, COL1A1, COL1A2, COL3A1, COL4A1, COL4A2, COL5A1, COL6A1, COL6A2, COL7A1, Collagen I, Collagen III, Collagen IV, Collagen V, Collagen VI, COMP, Cortisol, CORTISOL, CRELD1, CRP, CSF1, CSF1R, CTSK, CXCL1, CXCL10, CXCL11, CXCL12, CXCL2, CXCL8, CXCL9, DCN, DHEA, DKK 1, Dystroglycan, EDN1, EDNRA, EDNRB, Endothelin-1, EPO, ESRI, ESR2, Fetuin-A, Fetuin-B, FGA, FGB, FGF10, FGF19, FGF2, FGF21, FGF23, FGF6, FGF7, FGFR1, FGFR2, FGFR4, FGG, Fibroblast growth factor 15 (FGF15), Fibronectin, FLT1, FLT4, FN1, Follistatin, FSH, FSHR, Galectin-1 / LGALS1, Galectin-3 / LGALS3, Gastrin, GASTRIN, GCGR, GDF5, GH, GH (GROWTH HORMONE), GHR, Ghrelin, GHRH, GHRL, GIP, GLP-1, GLP-2, GLP1, GLP2, Glucagon, GLUCAGON, GLUT4, HCG, HEG1, Hepatic lipase, HGF, HMGB1, HSPG2, IBSP, ICAM1, ICOSLG, IFNB, IFNG, IGF1, IGF1R, IGF2, IGF2R, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, IHH, IL-10, IL-18, IL-1B, IL-22, IL-6, IL10, IL10RA, IL17A, IL17RA, ILIA, IL1B, IL1R1, IL1R2, IL22, IL22RA1, IL6, IL6R, INS, INSR, Insulin, Insulin-like growth factor 1 (IGF1), INSULIN-LIKE GROWTH FACTOR 1 (IGF1), INSULIN-LIKE GROWTH FACTOR 2 (IGF2), Integrin a7, Integrin 1D, Irisin, ITGA1, ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGAV, ITGB1, ITGB2, ITGB3, ITGB4, ITGB5, ITGB8, KDR, KLB, KLOTHO, 301645057.1LAMA1, LAMA2, LAMA4, LAMA5, LAMB1, LAMB 2, LAMC1, Laminin, LAMININ, LDLR, LECT2, LEP, LEPR, Leptin, LEPTIN, LH, LHR, Lipocalin-2, Lipoprotein lipase, LUB RICIN, LY96, MATN1, MATN3, MELATONIN, MMP1, MMP12, MMP13, MMP14, MMP2, MMP3, MMP7, MMP9, Motilin, MOTILIN, Myostatin (GDF8), MYOSTATIN / GDF8, NELLI, NIDI, NID2, Nitric oxide, Nitric oxide synthase (eNOS), NOTCH3, NPR 1, NPR 2, NPR 3, NR3C1 (GLUCOCORTICOID RECEPTOR), NR3C2 (MINERALOCORTICOID RECEPTOR), Omentin, OPG, Osteocalcin, OXTR, Oxyntomodulin, OXYTOCIN, Pancreatic polypeptide, Parathyroid hormone, PDCD1LG2, PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFRA, PDGFRB, Perlecan, PLG, POSTN, PRG4, PRLR, PROLACTIN, PROS1, PTH, PTH1R, PTHRP, PYY, RANKL, RBP4, RENIN, Resistin, RETINOL-BINDING PROTEIN 4, RSPO1, RSPO2, RSPO3, S100A8, S100A9, SCARB1, Sclerostin, SCUBE1, Secretin, SECRETIN, SELE, Selenoprotein P, SELP, SERPINE1, SHH, SIRT1, Somatostatin, SOMATOSTATIN, SOST, SPARC, SPP1, SSTR2, Tenascin-C, TESTOSTERONE, TGF-beta, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, THYROGLOBULIN, THYROID PEROXIDASE, Thyroxine (T4), THYROXINE (T4), TLL1, TLR1, TLR2, TLR4, TLR5, TLR6, TLR9, TNC, TNF, TNFRSF11A (RANK), TNFRSF11B (OPG), TNFRSF1A, TNFRSF1B, TNFSF11 (RANKL), TPO, Transferrin, TRANSTHYRETIN, Triiodothyronine (T3), TRIIODOTHYRONINE (T3), TSHR, uPA / PLAU, VASOPRESSIN (A VP), VCAM1, VCAN, VDR, VEGFA, VEGFB, VEGFC, VEGFD, Visfatin, VITAMIN D (CALCITRIOL), VITAMIN D BINDING PROTEIN (GC), VLDLR, VWF, WNT10B, WNT3A, WNT5A, a-Sarcoglycan, 0-Sarcoglycan, y-Sarcoglycan, and / or 6-Sarcoglycan. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for deconditioning additionally comprises one or more appended domains. In embodiments an appended domain is MOT-c.2. Viral Latency and Reactivation

[0210] In embodiments, the cellular reprogramming protein modulates the immune processes of viral latency and reactivation. In embodiments, the viral latency and reactivation is modulated in an infection selected from the group consisting of: herpesviruses, including herpes simplex virus types 1 and 2 (HSV-1, HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), and Kaposi’s sarcoma-associated herpesvirus (KSHV / HHV-8); retroviruses, including human immunodeficiency virus type 1 (HIV-1) and human T-cell 301645057.1leukemia virus type 1 (HTLV-1); hepatitis B virus (HBV) with covalently closed circular DNA (cccDNA) reservoirs; human papillomavirus (HPV); polyomaviruses, including JC virus (JCV) and BK virus (BKV); adenoviruses; and other viruses exhibiting latent, persistent, or smoldering infection states, including reactivation under conditions of immunosuppression, immune exhaustion, inflammation, or cellular stress.

[0211] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent viral latency and reactivation. In embodiments, the FC domain of the cellular reprogramming protein for viral latency and reactivation comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprises ACTH (POMC), ACTIVIN A, ACTIVIN B, ADAM10, ADAM17, ADAMTS1, ADAMTS4, Adenosine, ADGRE3, Adiponectin, ADIPONECTIN, ADIPOQ, ADORA2A, ADP, Adrenomedullin, AGER, AGER (RAGE), AGER / RAGE, Aggrecan, Agouti signaling protein (ASIP), Albumin, ALBUMIN, Aldosterone, ALDOSTERONE, Alpha-MSH (POMC-derived), AMH, AMHR2, AMP, Amylin, Amylin (IAPP), AMYLA°N (IAPP), Angiopoietin-like 3 (ANGPTL3), ANGIOTENSIN II, ANGIOTENSINOGEN, ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANGPTL6, ANGPTL8, ANP (NPPA), ANTI-MULLERIAN HORMONE (AMH), Apelin, Apolipoprotein A-I, Apolipoprotein B, Apolipoprotein C-III, Apolipoprotein E, AR, AREG, ARTN, ATP, AVPR1A, AVPR2, BDNF, Beta-defensin 1 (hBDl), Beta-defensin 2 (hBD2), Beta-defensin 3 (hBD3), BGN, Biglycan, Bile acids, BMP2, BMP4, BMP6, BMP7, BNP (NPPB), Bradykinin, Brevican, BTC, C-reactive protein, Cl, Clq, Clr, Cis, C2, C3, C3a, C3aRl, C4, C5, C5a, C5aRl / CD88, C5aR2, C6, C7, C8, C9, CALCITONIN, Calcitonin gene-related peptide (CGRP), cAMP, Carbon monoxide, Cathelicidin LL-37, CBG (SERPINA6), CCBE1, CCL11, CCL17, CCL19, CCL2, CCL20, CCL21, CCL27, CCL28, CCL3, CCL4, CCL5, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CD14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform,CD36, CD44, CD80, CD86, Ceramide, cGMP, Chemerin, Cholecystokinin, CHROMOGRANIN A, Claudin-1 (CLDN1), CLEC4E (MINCLE), CLEC4E / MINCLE, CLEC6A (Dectin-2), CLEC6A / Dectin-2, CLEC7A (Dectin-1), CLEC7A / Dectin-1, CLU, CNTF, COL18A1, COL1A1, COL3A1, COL4A1, COL4A2, COL5A1, COL6A1, COL7A1, Collagen I, Collagen III, Collagen V,301645057.1Collagen VI, Collagen VII, Collagen XII, Collagen XIV, Collagen XVII (BP180), Contactin-1, Contactin-2, Corneodesmosin (CDSN), Corticotropin-releasing hormone (CRH), Cortisol, CORTISOL, CR1 / CD35, CR2 / CD21, CRB1, CRP, CSF1, CTSB, CTSD, CX3CL1, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL2, CXCL8, CXCL9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, DCN, Decorin, Defensin alpha, Defensin beta, Desmocollin 1 (DSC1), Desmocollin 3 (DSC3), Desmoglein 1 (DSG1), Desmoglein 3 (DSG3), DHEA, DHH, DKK 1, Dopamine, E-cadherin (CDH1), EFEMP1, EFEMP2, EGF, EGFL8, EGFR, Elafin (PI3), Elastin, ELN, EMILIN1, EMILIN2, Endocannabinoid 2-AG, Endocannabinoid anandamide, Endothelin-1, Endothelin-1 (EDN1), Ephrin-Al, Ephrin-A2, Ephrin-A3, Ephrin-Bl, Ephrin-B2, Epinephrine, EPO, ERBB2, ERBB3, ERBB4, EREG, ESRI, ESR2, ESTRADIOL, F2R / PAR1, F2RL1 / PAR2, Factor B, Factor D, FAT3, FBN3, FCAR / CD89, FCGR1A / CD64, FCGR2A / CD32, FCGR3A / CD16a, FCGR3B / CD16b, Fetuin-A, Fetuin-B, FGF10, FGF19, FGF2, FGF21, FGF23, FGF6, FGF7, FGF7 (KGF), FGF8, FGFR1, FGFR2, FGFR3, FGFR4, Fibrillin- 1, Fibrillin-2, Fibrinogen, Fibroblast growth factor 15 (FGF15), Fibronectin, Fibulin-2, Fibulin-5, Filaggrin-processed NMF (contextual), FLT1, FLT1 (VEGFR1), FLT4 (VEGFR3), FN1, Follistatin, FSH, FSHR, Gastrin, GASTRIN, GCGR, GDNF, GH (GROWTH HORMONE), GHR, Ghrelin, GHRH, GHRL, GIP, GLP-1, GLP-2, GLP1, GLP2, Glucagon, GLUCAGON, GLUT4, GNRHR, HBEGF, HCG, Hepatic lipase, HGF, Histamine, HLA-DPB, HLA-DPB1, HLA-G, HMGB1, HSPG2, Hyaluronan, HYALURONAN, Hydrogen sulfide, ICAM1, ICOSLG, IFNA, IFNAR1, IFNAR2, IFNB, IFNG, IFNGR1, IFNGR2, IGF1, IGF1R, IGF2, IGF2R, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, IGHG4, IGLC1, IGLC7, IGLL5, IHH, IL-10, IL-12, IL-17A, IL-17F, IL-18, IL-1A, IL-1B, IL-22, IL-23, IL-25, IL-33, IL-6, IL-8, IL10, IL10RA, IL10RB, IL12RB1, IL12RB2, IL15, IL17A, IL17RA, IL17RC, IL18R1, IL18RAP, ILIA, IL1B, IL1R1, IL1R2, IL22, IL22RA1, IL33R (ST2 / IL1RL1), IL6, IL6R, IL7, IL8, INHIBIN A, INHIBIN B, INS, INSR, Insulin, Insulin-like growth factor 1 (IGF1), INSULIN-LIKE GROWTH FACTOR 1 (IGF1), INSULIN-LIKE GROWTH FACTOR 2 (IGF2), Integrin alpha3 (ITGA3), Integrin alpha6 (ITGA6), Integrin betal (ITGB1), Integrin beta4 (ITGB4), Irisin, ITGA1, ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGA9, ITGAE, ITGAM / CDllb, ITGAV, ITGAX / CDllc, ITGB1, ITGB2 / CD18, ITGB3, ITGB4, ITGB5, ITGB7, ITGB8, IZUMO1, JUNO, Kallidin, Kallikrein KLK14, Kallikrein KLK5, Kallikrein KLK7, KDR, KDR (VEGFR2), KISS1R, KISSPEPTIN, KITLG (SCF), KLB, L1CAM, Lactoferrin, LAMA3, LAMA4, LAMA5, LAMB1, LAMC1, Laminin, LAMININ, Laminin-332, Laminin-511, Laminin-521, LBP, LDLR, LECT2, LEKTI (SPINK5), LEP, LEPR, Leptin, LEPTIN, Leukotriene B4, Leukotriene 301645057.1C4, Leukotriene D4, Leukotriene E4, LGALS1, LGALS3, LH, LHR, LIF, Lipocalin-2, Lipoprotein lipase, Lipoxin A4, Lipoxin B4, LPS-binding protein, LRP8, LTBP1, LTBP2, LTBP4, Lumican, LY86 / MD-1, LY96, LY96 (MD-2), LY96 / MD-2, Lysophosphatidic acid, Lysozyme, LYVE1, MADCAM1, Mannose-binding lectin, Maresin 1, MASP2, Melatonin, MELATONIN, MMP1, MMP12, MMP13, MMP14, MMP2, MMP3, MMP7, MMP8, MMP9, Motilin, MOTILIN, MSR1 / SR-A1, MUC1, MUC16, MUC2, MUC4, MUC5AC, Myostatin (GDF8), N-cadherin (CDH2), NCAM1, NELL2, Netrin-1, Netrin-3, Netrin-4, Neurexin-1, Neurexin-2, Neurexin-3, Neurocan, Neuroligin-1, Neuroligin-2, Neuroligin-3, Neuropeptide Y, NGF, NIDI, NID2, Nidogen, Nidogen-1, Nidogen-2, Nitric oxide, Norepinephrine, NOTCH 1, NOTCH2NLB, NR3C1 (GLUCOCORTICOID RECEPTOR), NR3C2 (MINERALOCORTICOID RECEPTOR), NrCAM, NRTN, NT-3, NT-4, Occludin (OCLN), Omentin, OPG, Osteocalcin, Osteopontin, OXTR, Oxyntomodulin, OXytocin, OXYTOCIN, P2RX7, PALI, Pancreatic polypeptide, Parathyroid hormone, PDCD1LG2, PDCD1LG2 (PD-L2), PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFRA, PDGFRB, PDPN (Podoplanin), PECAM1, Pentraxins PTX3, Periostin, Perlecan, Peroxynitrite, PGR, Plasminogen, Plateletactivating factor (PAF), PLG, POSTN, PRLR, PROGESTERONE, PROLACTIN, Properdin, Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), Prostaglandin F2a (PGF2a), Protectin DI, PSPN, PTH, PTH1R, PTHRP, PTX3, PYY, RANKL, RBP4, Reactive oxygen species, Reelin, RELAXIN, RELN, RENIN, Resistin, Resolvin DI, Resolvin D2, Resolvin El, RETINOL-BINDING PROTEIN 4, RP105 / TLR5L, RSPO1, RSPO2, RSPO3, S100A1, S100A5, S100A6, S100A7, S100A7 (Psoriasin), S100A8, S100A9, SCARB1, Sclerostin, Secretin, SECRETIN, Secretory IgA, SELE, SELE (E-selectin), Selenoprotein P, SELP, SELP (P-selectin), Semaphorin3A, Semaphorin3F, Semaphorin4D, Serotonin, SERPINE1, Serum amyloid A, SHH, SIGLEC1, SIGLEC10, SIGLEC14, SIGLEC7, SIGLEC9, SIRT1, Slitl, Slit2, Slit3, SLPI, Somatostatin, SOMATOSTATIN, SPARC, Sphingosine- 1 -phosphate, SPON1, SPP1, SSTR2, Substance P, Tenascin-C, Tenascin-R, Tenascin-X, TESTOSTERONE, TGF-beta, TGF-betal (TGFB1), TGF-beta2 (TGFB2), TGF-beta3 (TGFB3), TGFA, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, THBS3, Thrombin, Thromboxane A2, THYROGLOBULIN, THYROID PEROXIDASE, Thyroxine (T4), THYROXINE (T4), TIE2, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TNC, TNF, TNFRSF1A, TNFRSF1B, TPO, Transferrin, TRANSTHYRETIN, TREM1, TREM2, Triiodothyronine (T3), TRIIODOTHYRONINE (T3), TSHR, TSLP, TSLP receptor (TSLPR / CRLF2), UDP, UTP, Vasoactive intestinal peptide, VASOPRESSIN (A VP), VCAM1, VCAN, VDR, VEGFA, VEGFB, VEGFC, VEGFD, VEGFR2 (KDR), VEGFR3 301645057.1(FLT4), Versican, Visfatin, VITAMIN D (CALCITRIOL), VITAMIN D BINDING PROTEIN (GC), Vitronectin, VLDLR, VTCN1, VTCN1 (B7-H4), VTCN1 / B7-H4, WNT1, WNT10A, WNT10B, WNT3, WNT3A, WNT4, WNT5A, WNT7A, WNT7B, ZP3, and / or ZP4. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for viral latency and reactivation additionally comprises one or more appended domains. In embodiments an example appended domain is LL-37.3. Metabolic Dysfunction

[0212] In embodiments, the cellular reprogramming protein modulates the immune processes of metabolic dysfunction. In embodiments, the metabolic dysfunction is selected from the group consisting of: obesity; insulin resistance; impaired glucose tolerance; type 2 diabetes mellitus; metabolic syndrome; dyslipidemia, including hypertriglyceridemia and low high-density lipoprotein (HDL); nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH); hepatic insulin resistance; adipose tissue inflammation; ectopic lipid deposition; lipotoxicity; sarcopenic obesity; atherosclerosis and cardiometabolic inflammation; hypertension with inflammatory features; hyperuricemia with inflammatory sequelae; cachexia; lipodystrophy; mitochondrial dysfunction-associated metabolic disease; and post-inflammatory or treatment-induced metabolic disturbance.

[0213] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent metabolic dysfunction. In embodiments, the FC domain of the cellular reprogramming protein for metabolic dysfunction comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprises AC AN, ACTH (POMC), ACTIVIN A, ACTIVIN B, ADAM10, ADAM12, ADAM17, ADAMTS1, ADAMTS4, ADAMTS5, Adiponectin, ADIPONECTIN, ADIPOQ, Adrenomedullin, AGER, AGER (RAGE), Agouti signaling protein (ASIP), Agrin, AGTR1, AGTR2, Albumin, ALBUMIN, Aldosterone, ALDOSTERONE, Alpha-MSH (POMC-derived), AMH, AMHR2, Amylin, Amylin (IAPP), AMYLA°N (IAPP), Angiopoietin-like 3 (ANGPTL3), ANGIOTENSIN II, ANGIOTENSINOGEN, ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANGPTL6, ANGPTL8, ANP (NPPA), ANTI-MULLERIAN HORMONE (AMH), Apelin, Apolipoprotein301645057.1A-I, Apolipoprotein B, Apolipoprotein C-III, Apolipoprotein E, AR, AREG, AVPR1A, AVPR2, BDNF, Beta-defensin 1 (hBDl), Beta-defensin 2 (hBD2), Beta-defensin 3 (hBD3), BGLAP, BGN, Biglycan, Bile acids, BMP2, BMP4, BMP6, BMP7, BNP (NPPB), BTC, Clq, C3, C3AR1, C4, C5, C5AR1, CALCITONIN, Cathelicidin LL-37, CBG (SERPINA6), CCBE1, CCL11, CCL17, CCL19, CCL2, CCL20, CCL21, CCL25, CCL27, CCL28, CCL5, CCR10, CCR2, CCR4, CCR5, CCR6, CCR7, CCR9, CD14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform„ CD36, CD44, CD80, CD86, Chemerin, Cholecystokinin, CHROMOGRANIN A, Claudin-1 (CLDN1), CLEC4E (MINCLE), CLEC6A (Dectin-2), CLEC7A (Dectin-1), COL11A1, COL12A1, COL14A1, COL15A1, COL18A1, COL1A1, COL1A2, COL3A1, COL4A1, COL4A2, COL5A1, COL6A1, COL6A2, COL7A1, Collagen I, Collagen III, Collagen IV, Collagen V, Collagen VI, Collagen VII, Collagen XII, Collagen XIV, Collagen XVII (BP180), Collagen XVIII, COMP, Corneodesmosin (CDSN), Cortisol, CORTISOL, CRELD1, CRP, CSF1, CSF1R, CTSB, CTSD, CTSK, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL2, CXCL8, CXCL9, CXCR2, CXCR3, CXCR4, CXCR5, DCN, Decorin, Defensin alpha, Defensin beta, Desmocollin 1 (DSC1), Desmocollin 3 (DSC3), Desmoglein 1 (DSG1), Desmoglein 3 (DSG3), DHEA, DKK 1, Dystroglycan, E-cadherin (CDH1), EDN1, EDNRA, EDNRB, EFEMP2, EGF, EGFR, Elafin (PI3), Elastin, ELN, EMILIN 1, EMILIN2, Endothelin-1, Endothelin-1 (EDN1), EPO, ERBB2, ERBB3, ERBB4, EREG, ESRI, ESR2, ESTRADIOL, Factor B, Factor D, FBN3, Fetuin-A, Fetuin-B, FGA, FGB, FGF10, FGF19, FGF2, FGF21, FGF23, FGF6, FGF7, FGF7 (KGF), FGF8, FGFR1, FGFR2, FGFR3, FGFR4, FGG, Fibrillin-1, Fibrillin-2, Fibroblast growth factor 15 (FGF15), Fibronectin, Fibulin-2, Fibulin-5, Filaggrin-processed NMF (contextual), FLT1, FLT1 (VEGFR1), FLT4, FLT4 (VEGFR3), FN1, Follistatin, FSH, FSHR, Galectin-1 / LGALS1, Galectin-3 / LGALS3, Gastrin, GASTRIN, GCGR, GDF5, GH, GH (GROWTH HORMONE), GHR, Ghrelin, GHRH, GHRL, GIP, GLP-1, GLP-2, GLP1, GLP2, Glucagon, GLUCAGON, GLUT4, GNRHR, HBEGF, HCG, HEG1, Hepatic lipase, HGF, HLA-G, HMGB1, HSPG2, HYALURONAN, IBSP, ICAM1, ICOSLG, IFNB, IFNG, IGF1, IGF1R, IGF2, IGF2R, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, IHH, IL-10, IL-17A, IL-17F, IL-18, IL-1A, IL-1B, IL-22, IL-23, IL-25, IL-33, IL-6, IL-8, IL10, IL10RA, IL15, IL17A, IL17RA, IL17RC, ILIA, IL1B, IL1R1, IL1R2, IL22, IL22RA1, IL33R (ST2 / IL1RL1), IL6, IL6R, IL7, IL8, INHIBIN A, INHIBIN B, INS, INSR, Insulin, Insulin-like growth factor 1 (IGF1), INSULIN-LIKE GROWTH FACTOR 1 (IGF1), INSULIN-LIKE GROWTH FACTOR 2 (IGF2), Integrin alpha3 (ITGA3), Integrin alpha6 (ITGA6), Integrin betal (ITGB1), Integrin beta4 (ITGB4), Integrin a7, Integrin piD, Irisin, 301645057.1ITGA1, ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGA9, ITGAE, ITGAV, ITGB1, ITGB2, ITGB3, ITGB4, ITGB5, ITGB7, ITGB8, IZUMO1, JUNO, Kallikrein KLK14, Kallikrein KLK5, Kallikrein KLK7, KDR, KDR (VEGFR2), KISS1R, KISSPEPTIN, KITLG (SCF), KLB, KLOTHO, Lactoferrin, LAMA1, LAMA2, LAMA3, LAMA4, LAMA5, LAMB1, LAMB2, LAMC1, Laminin, LAMININ, Laminin- 111, Laminin-332, Laminin-511, Laminin-521, LBP, LDLR, LECT2, LEKTI (SPINK5), LEP, LEPR, Leptin, LEPTIN, LGALS1, LGALS3, LH, LHR, LIF, Lipocalin-2, Lipoprotein lipase, LTBP2, LTBP4, LUBRICIN, Lumican, LY96, LY96 (MD-2), Lysozyme, LYVE1, MADCAM1, MATN1, MATN3, MELATONIN, MMP1, MMP12, MMP13, MMP14, MMP2, MMP3, MMP7, MMP9, Motilin, MOTILIN, MUC1, MUC16, MUC2, MUC4, MUC5AC, Myostatin (GDF8), MYOSTATIN / GDF8, N-cadherin (CDH2), NELLI, NIDI, NID2, Nidogen-1, Nidogen-2, Nitric oxide, Nitric oxide synthase (eNOS), NODI, NOD2, NOTCH3, NPR 1, NPR 2, NPR 3, NR3C1 (GLUCOCORTICOID RECEPTOR), NR3C2 (MINERALOCORTICOID RECEPTOR), Occludin (OCLN), Omentin, OPG, Osteocalcin, Osteopontin, OXTR, Oxyntomodulin, OXytocin, OXYTOCIN, Pancreatic polypeptide, Parathyroid hormone, PDCD1LG2, PDCD1LG2 (PD-L2), PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFRA, PDGFRB, PDPN (Podoplanin), PECAM1, Periostin, Perlecan, PGR, PLG, POSTN, PRG4, PRLR, PROGESTERONE, PROLACTIN, Properdin, PROS1, PTH, PTH1R, PTHRP, PYY, RANKL, RBP4, REG3A, REG3G, RELAXIN, RELN, RENIN, Resistin, RETINOL-BINDING PROTEIN 4, RSPO1, RSPO2, RSPO3, S100A7 (Psoriasin), S100A8, S100A9, SCARB1, Sclerostin, SCUBE1, Secretin, SECRETIN, Secretory IgA, SELE, SELE (E-selectin), Selenoprotein P, SELP, SELP (P-selectin), SERPINE1, SHH, SIRT1, SLPI, Somatostatin, SOMATOSTATIN, SOST, SPARC, SPON1, SPP1, SSTR2, Tenascin-C, Tenascin-X, TESTOSTERONE, TGF-beta, TGF-betal, TGF-betal (TGFB1), TGF-beta2, TGF-beta2 (TGFB2), TGF-beta3, TGF-beta3 (TGFB3), TGFA, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, THYROGLOBULIN, THYROID PEROXIDASE, Thyroxine (T4), THYROXINE (T4), TIE2, TLL1, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR9, TNC, TNF, TNFRSF11A (RANK), TNFRSF11B (OPG), TNFRSF1A, TNFRSF1B, TNFSF11 (RANKL), TPO, Transferrin, TRANSTHYRETIN, Triiodothyronine (T3), TRIIODOTHYRONINE (T3), TSHR, TSLP, TSLP receptor (TSLPR / CRLF2), uPA / PLAU, VASOPRESSIN (A VP), VCAM1, VCAN, VDR, VEGFA, VEGFB, VEGFC, VEGFD, VEGFR2 (KDR), VEGFR3 (FLT4), Versican, Visfatin, VITAMIN D (CALCITRIOL), VITAMIN D BINDING PROTEIN (GC), Vitronectin, VLDLR, VTCN1, VTCN1 (B7-H4), VWCE, VWF, WNT10A, WNT10B, WNT3, WNT3A, WNT4, WNT5A, WNT9B, ZP3, ZP4, 301645057.1a-Sarcoglycan, P-Sarcoglycan, y-Sarcoglycan, and / or 6-Sarcoglycan. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for metabolic dysfunction additionally comprises one or more appended domains. Example appended domains are GLP1 or GIP.4. Barrier Dysfunction

[0214] In embodiments, the cellular reprogramming protein modulates the immune processes of barrier dysfunction. In embodiments, the barrier dysfunction is selected from the group consisting of: epithelial, endothelial, or mixed barrier impairment of the skin, gastrointestinal tract, respiratory tract, genitourinary tract, ocular surface, hepatobiliary system, and central nervous system; tight-j unction disruption; increased paracellular permeability; impaired mucus or surfactant layers; defective antimicrobial peptide production; dysbiosis-associated barrier loss; vascular leak; and edema formation.

[0215] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent barrier dysfunction. In embodiments, the FC domain of the cellular reprogramming protein for barrier dysfunction comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprises ADAMIO, ADAM17, ADAMTS1, ADAMTS4, ADAMTS5, Adenosine, ADGRE3, ADORA2A, ADP, AGER, AGER (RAGE), AGER / RAGE, Agouti signaling protein (ASIP), AGRIN, AGTR1, AGTR2, ALDOSTERONE, Alpha-MSH (POMC -derived), AMP, ANGIOTENSIN II, ANGIOTENSINOGEN, ANGPT1, ANGPT2, ANP (NPPA), AREG, ATP, AVPR1A, AVPR2, Beta-defensin 1 (hBDl), Beta-defensin 2 (hBD2), Beta-defensin 3 (hBD3), BGN, Biglycan, BMP2, BMP4, BMP7, BNP (NPPB), BPIFA1, Bradykinin, BTC, C-reactive protein, Cl, Clq, Clr, Cis, C2, C3, C3a, C3aRl, C3AR1, C4, C5, C5a, C5AR1, C5aRl / CD88, C5aR2, C6, C7, C8, C9, Calcitonin gene-related peptide (CGRP), cAMP, Carbon monoxide, Cathelicidin LL-37, CCBE1, CCL11, CCL17, CCL19, CCL2, CCL20, CCL21, CCL25, CCL27, CCL28, CCL3, CCL4, CCL5, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CD 14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform, CD36, CD44, CD80, CD86, Ceramide, cGMP, Cholecystokinin, Claudin-1301645057.1(CLDN1), CLEC4E, CLEC4E (MINCLE), CLEC4E / MINCLE, CLEC6A, CLEC6A (Dectin-2), CLEC6A / Dectin-2, CLEC7A, CLEC7A (Dectin-1), CLEC7A / Dectin-1, COL18A1, COL1A1, COL3A1, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL5A1, COL6A1, COL7A1, Collagen I, Collagen III, Collagen IV, Collagen V, Collagen VI, Collagen VII, Collagen XII, Collagen XIV, Collagen XVII (BP180), Collagen XVIII, Corneodesmosin (CDSN), Corticotropin-releasing hormone (CRH), CR1 / CD35, CR2 / CD21, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL2, CXCL8, CXCL9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, DCN, Decorin, Defensin alpha, Defensin beta, Desmocollin 1 (DSC1), Desmocollin 3 (DSC3), Desmoglein 1 (DSG1), Desmoglein 3 (DSG3), Dopamine, E-cadherin (CDH1), EFEMP2, EGF, EGFR, Elafin (PI3), Elastin, ELN, EMILIN1, EMILIN2, Endocannabinoid 2-AG, Endocannabinoid anandamide, Endothelin-1 (EDN1), Epinephrine, ERBB2, ERBB3, ERBB4, EREG, ERYTHROPOIETIN (EPO), F2R / PAR1, F2RL1 / PAR2, Factor B, Factor D, FBN1, FBN3, FCAR / CD89, FCGR1A / CD64, FCGR2A / CD32, FCGR3A / CD16a, FCGR3B / CD16b, FGF10, FGF19, FGF2, FGF21, FGF23, FGF7, FGF7 (KGF), FGFR1, FGFR2, FGFR3, FGFR4, Fibrillin- 1, Fibrillin-2, Fibrinogen, Fibronectin, Fibulin-2, Fibulin-5, Filaggrin-processed NMF (contextual), FLT1, FLT1 (VEGFR1), FLT4 (VEGFR3), FN1, Gastrin, Ghrelin, GIP, GLP-1, GLP-2, HBEGF, Histamine, HLA-DPB, HLA-DPB1, HMGB1, HSPG2, HYALURONAN, Hydrogen sulfide, ICAM1, ICOSLG, IFNA, IFNAR1, IFNAR2, IFNB, IFNG, IFNGR1, IFNGR2, IGHG4, IGLC1, IGLC7, IGLL5, IHH, IL-10, IL-12, IL-17A, IL-17F, IL-18, IL-1A, IL-1B, IL-22, IL-23, IL-25, IL-33, IL-6, IL-8, IL10, IL10RA, IL10RB, IL12RB1, IL12RB2, IL13, IL13RA1, IL15, IL17A, IL17RA, IL17RC, IL18R1, IL18RAP, ILIA, IL1B, IL1R1, IL1R2, IL1RL1 (ST2), IL22, IL22RA1, IL25, IL33, IL33R (ST2 / IL1RL1), IL6, IL6R, IL7, IL8, Integrin alpha3 (ITGA3), Integrin alpha6 (ITGA6), Integrin betal (ITGB1), Integrin beta4 (ITGB4), ITGA1, ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGA9, ITGAE, ITGAM / CDllb, ITGAV, ITGAX / CDllc, ITGB1, ITGB2 / CD18, ITGB3, ITGB4, ITGB5, ITGB6, ITGB7, ITGB8, Kallidin, Kallikrein KLK14, Kallikrein KLK5, Kallikrein KLK7, KDR, KDR (VEGFR2), KITLG (SCF), KLB, KLOTHO, Lactoferrin, LAMA3, LAMA4, LAMA5, LAMB1, LAMB2, LAMC1, Laminin- 111, Laminin-332, Laminin-511, Laminin-521, LBP, LEKTI (SPINK5), Leukotriene B4, Leukotriene C4, Leukotriene D4, Leukotriene E4, Lipoxin A4, Lipoxin B4, LPS-binding protein, LTBP1, LTBP2, LTBP4, Lumican, LY86 / MD-1, LY96, LY96 (MD-2), LY96 / MD-2, Lysophosphatidic acid, Lysozyme, LYVE1, MADCAM1, Mannose-binding lectin, Maresin 1, MASP2, Melatonin, MMP1, MMP12, MMP13, MMP14, MMP2, MMP3, MMP7, MMP8, MMP9, Motilin, MSR1 / SR-A1, MUC1, MUC16, MUC2, MUC4, MUC5AC, 301645057.1MUC5B, N-cadherin (CDH2), Neuropeptide Y, NIDI, NID2, Nidogen-1, Nidogen-2, Nitric oxide, NODI, NOD2, Norepinephrine, Occludin (OCLN), Osteopontin, P2RX7, PAI-1, PDCD1LG2, PDCD1LG2 (PD-L2), PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFRA, PDGFRB, PDPN (Podoplanin), PECAM1, Pentraxins PTX3, Periostin, Perlecan, Peroxynitrite, Plasminogen, Platelet-activating factor (PAF), PLG, POSTN, Properdin, Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), Prostaglandin F2a (PGF2a), Protectin DI, PTH, PTH1R, PTX3, PYY, Reactive oxygen species, REG3A, REG3G, RELN, RENIN, Resolvin DI, Resolvin D2, Resolvin El, RP105 / TLR5L, RSPO1, RSPO2, RSPO3, S100A1, S100A6, S100A7, S100A7 (Psoriasin), S100A8, S100A9, SCGB1A1, Secretin, Secretory IgA, SELE, SELE (E-selectin), SELP, SELP (P-selectin), Serotonin, SERPINE1, Serum amyloid A, SFTPA1, SFTPA2, SFTPB, SFTPC, SFTPD, SHH, SIGLEC1, SIGLEC10, SIGLEC14, SIGLEC7, SIGLEC9, SLPI, Somatostatin, SPARC, Sphingosine- 1 -phosphate, SPON1, SPP1, Substance P, Tenascin-C, Tenascin-X, TGF-betal, TGF-betal (TGFB1), TGF-beta2, TGF-beta2 (TGFB2), TGF-beta3, TGF-beta3 (TGFB3), TGFA, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, THBS3, Thrombin, Thromboxane A2, TIE2, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TNC, TNF, TNFRSF1A, TNFRSF1B, TREM1, TREM2, TSLP, TSLP receptor (TSLPR / CRLF2), UDP, UMOD, UTP, Vasoactive intestinal peptide, VASOPRESSIN (A VP), VCAM1, VCAN, VEGFA, VEGFB, VEGFC, VEGFD, VEGFR2 (KDR), VEGFR3 (FLT4), Versican, VITAMIN D (CALCITRIOL), Vitronectin, VTCN1, VTCN1 (B7-H4), VTCN1 / B7-H4, VWCE, WNT10A, WNT10B, WNT3, WNT3A, WNT4, WNT5A, WNT7B, and / or WNT9B . The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for barrier dysfunction additionally comprises one or more appended domains. An is Ac-SDKQKK.5. Digestive Disorders

[0216] In embodiments, the cellular reprogramming protein modulates the immune processes of digestive disorders. In embodiments, the digestive disorders is selected from the group consisting of: inflammatory bowel diseases; infectious or post-infectious enteritis / colitis; celiac disease and gluten-related disorders; eosinophilic gastrointestinal diseases; irritable bowel syndrome with inflammatory features; microscopic colitis; short-bowel syndrome and environmental enteric dysfunction; radiation- or chemotherapy-induced mucositis; immune checkpoint inhibitor-associated enterocolitis; graft-versus-host disease of the gastrointestinal tract; chronic pancreatitis and autoimmune pancreatitis; biliary and cholangiopathic disorders; peptic ulcer disease and H. pylori-associated gastritis; functional dyspepsia with inflammatory 301645057.1features; small intestinal bacterial overgrowth or dysbiosis-associated disorders; and intestinal fibrosis or stricturing disease.

[0217] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent digestive disorders. In embodiments, the FC domain of the cellular reprogramming protein for digestive disorders comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprise ADAMIO, ADAM17, ADAMTS1, ADAMTS4, ADAMTS5, Adenosine, ADGRE3, ADORA2A, ADP, AGER, AGER / RAGE, Agrin, AMP, ANGPT1, ANGPT2, AREG, ATP, BGN, Biglycan, BMP2, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, Bradykinin, BTC, C-reactive protein, Cl, Clq, Clr, Cis, C2, C3, C3a, C3aRl, C4, C5, C5a, C5aRl / CD88, C5aR2, C6, C7, C8, C9, Calcitonin gene-related peptide (CGRP), cAMP, Carbon monoxide, Cathelicidin LL-37, CCBE1, CCL1, CCL10, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL2, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CD 14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform, CD36, CD44, CD80, CD86, Ceramide, cGMP, Cholecystokinin, CLEC4E (MINCLE), CLEC4E / MINCLE, CLEC6A (Dectin-2), CLEC6A / Dectin-2, CLEC7A (Dectin-1), CLEC7A / Dectin-1, COL18A1, COL1A1, COL3A1, COL4A1, COL4A2, COL5A1, COL6A1, Collagen 1, Collagen 10, Collagen 11, Collagen 12, Collagen 13, Collagen 14, Collagen 15, Collagen 16, Collagen 17, Collagen 18, Collagen 19, Collagen 2, Collagen 20, Collagen 21, Collagen 22, Collagen 23, Collagen 24, Collagen 25, Collagen 26, Collagen 27, Collagen 28, Collagen 3, Collagen 4, Collagen 5, Collagen 6, Collagen 7, Collagen 8, Collagen 9, Collagen I, Collagen II, Collagen III, Collagen IV, Collagen V, Collagen VI, Collagen VII, Collagen XVIII, Corticotropin-releasing hormone (CRH), CR1 / CD35, CR2 / CD21, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, DCN, Decorin, Defensin alpha, Defensin beta, Delta-like 1, Delta-like 4, DHH, DLL4, Dopamine, EGF, EGFR, EMILIN 1, EMILIN2, Endocannabinoid 2- AG, Endocannabinoid anandamide, Epinephrine, ERBB2, EREG, F10, Fll, F12, F2, F2R / PAR1,301645057.1F2RL1 / PAR2, F3, F5, F7, F8, F9, Factor B, Factor D, FCAR / CD89, FCGR1A / CD64, FCGR2A / CD32, FCGR3A / CD16a, FCGR3B / CD16b, FGA, FGB, FGF1, FGF10, FGF11, FGF12, FGF13, FGF14, FGF15, FGF16, FGF17, FGF18, FGF19, FGF2, FGF20, FGF21, FGF22, FGF23, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, FGFR1, FGFR2, FGFR4, FGG, Fibrinogen, Fibronectin, FLT1 (VEGFR1), FLT4 (VEGFR3), FN1, GAL1 / LGALS1, GAL3 / LGALS3, Gastrin, Ghrelin, GIP, GLP-1, GLP-2, HBEGF, Histamine, HLA-DPB, HLA-DPB1, HMGB1, HSPG2, HYALURONAN, Hydrogen sulfide, ICAM1, ICOSLG, IFNA, IFNAR1, IFNAR2, IFNB, IFNG, IFNGR1, IFNGR2, IGF1, IGF2, IGHG4, IGLC1, IGLC7, IGLL5, IHH, IL-1, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-17A, IL-17F, IL-18, IL-19, IL-1A, IL-1B, IL-2, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-3, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL10, IL10RA, IL10RB, IL12RB1, IL12RB2, IL15, IL17A, IL17RA, IL17RC, IL18R1, IL18RAP, IL1B, IL1R1, IL1R2, IL22, IL22RA1, IL6, IL6R, IL7, ITGA1, ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGA9, ITGAE, ITGAM / CDllb, ITGAV, ITGAX / CDllc, ITGB1, ITGB2 / CD18, ITGB3, ITGB4, ITGB5, ITGB7, Jaggedl, Jagged2, Kallidin, KDR (VEGFR2), Lactoferrin, LAMA4, LAMA5, LAMB1, LAMC1, Laminin, Laminin- 111, Laminin-332, Laminin-511, Laminin-521, LBP, Leukotriene B4, Leukotriene C4, Leukotriene D4, Leukotriene E4, LIF, Lipoxin A4, Lipoxin B4, LPS-binding protein, LTA, LTB, LTBP1, Lumican, LY86 / MD-1, LY96 (MD-2), LY96 / MD-2, Lysophosphatidic acid, Lysozyme, LYVE1, MADCAM1, Mannose-binding lectin, Maresin 1, MASP2, Melatonin, MMP1, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP18, MMP19, MMP2, MMP20, MMP21, MMP22, MMP23, MMP24, MMP25, MMP26, MMP27, MMP28, MMP3, MMP4, MMP5, MMP6, MMP7, MMP8, MMP9, Motilin, MSR1 / SR-A1, MUC1, MUC2, MUC5AC, Neuropeptide Y, NIDI, NID2, Nidogen, Nidogen-1, Nidogen-2, Nitric oxide, NODI, NOD2, Norepinephrine, Osteopontin, P2RX7, PALI, PDCD1LG2, PDCD1LG2 (PD-L2), PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFC, PDGFD, PDGFRA, PDGFRB, PDPN (Podoplanin), PECAM1, Pentraxins PTX3, Periostin, Perlecan, Peroxynitrite, Plasminogen, Platelet-activating factor (PAF), PLG, POSTN, Properdin, Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), Prostaglandin F2a (PGF2a), Protectin DI, PTX3, PYY, Reactive oxygen species, REG3A, REG3G, RELN, Resolvin DI, Resolvin D2, Resolvin El, RP105 / TLR5L, RSPO1, RSPO2, RSPO3, RSPO4, S100A1, S100A6, S100A7, S100A8, S100A9, Secretin, Secretory IgA, SELE, SELP, Serotonin, SERPINE1, Serum amyloid A, SHH, SIGLEC1, SIGLEC10, SIGLEC14, SIGLEC7, SIGLEC9, Somatostatin, SPARC, Sphingosine- 1 -phosphate, SPON1, SPP1, Substance P, Tenascin-C, 301645057.1Tenascin-X, TGF-betal, TGF-beta2, TGF-beta3, TGFA, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, THBS3, Thrombin, Thrombospondin- 1, Thrombospondin-2, Thromboxane A2, TIE2, TIMP1, TIMP2, TIMP3, TIMP4, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TNC, TNF, TNFRSF1A, TNFRSF1B, TNFSF10, TNFSF11, TNFSF12, TNFSF13, TNFSF14, TNFSF15, TNFSF4, TNFSF8, TNFSF9, TREM1, TREM2, UDP, UTP, Vasoactive intestinal peptide, VCAM1, VCAN, VEGFA, VEGFB, VEGFC, VEGFD, Versican, Vitronectin, VTCN1 (B7-H4), VTCN1 / B7-H4, VWCE, VWF, WNT1, WNT10A, WNT10B, WNT11, WNT16, WNT2, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, and / or WNT9B. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for digestive disorders additionally comprises one or more appended domains. An example appended domain is GLP-2.6. Cardiovascular Disease

[0218] In embodiments, the cellular reprogramming protein modulates the immune processes of cardiovascular disease. In embodiments, the cardiovascular disease is selected from the group consisting of: atherosclerosis and atherothrombosis; plaque inflammation and vulnerability; coronary artery disease including acute coronary syndromes and chronic coronary syndromes; ischemia-reperfusion injury; myocardial infarction and adverse post-infarction remodeling; myocarditis; heart failure with reduced or preserved ejection fraction; cardiomyopathy with inflammatory features; microvascular dysfunction; arrhythmia with inflammatory or fibrotic substrates; peripheral artery disease; aortic disease including aneurysm and dissection; venous thromboembolism; pulmonary hypertension with inflammatory vascular remodeling; transplant vasculopathy; endocarditis; pericarditis; and device- or graft-associated vascular inflammation.

[0219] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent cardiovascular disease. In embodiments, the FC domain of the cellular reprogramming protein for cardiovascular disease comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprises ACTH (POMC), ADAMIO, AD AMU, ADAMTS1,301645057.1ADAMTS4, Adenosine, ADGRE3, Adiponectin, ADIPONECTIN, ADIPOQ, ADORA2A, ADP, Adrenomedullin, AGER, AGER / RAGE, AGTR1, AGTR2, Albumin, ALBUMIN, Aldosterone, ALDOSTERONE, AMH, AMP, Amylin, Amylin (IAPP), AMYLA°N (IAPP), Angiopoietin-like 3 (ANGPTL3), ANGIOTENSIN II, ANGIOTENSINOGEN, ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANGPTL6, ANGPTL8, ANP (NPPA), Apelin, Apolipoprotein A-I, Apolipoprotein B, Apolipoprotein C-III, Apolipoprotein E, AR, ATP, AVPR1A, AVPR2, BDNF, BGN, Bile acids, BMP2, BMP4, BMP7, BNP (NPPB), Bradykinin, C-reactive protein, Cl, Clq, Clr, Cis, C2, C3, C3a, C3aRl, C3AR1, C4, C5, C5a, C5AR1, C5aRl / CD88, C5aR2, C6, C7, C8, C9, CALCITONIN, Calcitonin gene-related peptide (CGRP), cAMP, Carbon monoxide, Cathelicidin LL-37, CBG (SERPINA6), CCL19, CCL2, CCL20, CCL21, CCL3, CCL4, CCL5, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CD 14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 41g-isoform, CD36, CD80, CD86, Ceramide, cGMP, Chemerin, Cholecystokinin, CHROMOGRANIN A, CLEC4E / MINCLE, CLEC6A / Dectin-2, CLEC7A / Dectin-1, COL18A1, COL1A1, COL1A2, COL3A1, COL4A1, COL4A2, COL5A1, COL6A1, COL6A2, COL7A1, Collagen I, Collagen III, Collagen IV, Corticotropin-releasing hormone (CRH), Cortisol, CORTISOL, CR1 / CD35, CR2 / CD21, CRELD1, CRP, CXCL1, CXCL10, CXCL11, CXCL12, CXCL2, CXCL8, CXCL9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, DCN, Defensin alpha, Defensin beta, DHEA, DKK 1, Dopamine, EDN1, EDNRA, EDNRB, Endocannabinoid 2- AG, Endocannabinoid anandamide, Endothelin-1, Epinephrine, EPO, ESRI, ESR2, F2R / PAR1, F2RL1 / PAR2, Factor B, Factor D, FCAR / CD89, FCGR1A / CD64, FCGR2A / CD32, FCGR3A / CD16a, FCGR3B / CD16b, Fetuin-A, Fetuin-B, FGA, FGB, FGF10, FGF19, FGF2, FGF21, FGF23, FGF6, FGF7, FGFR1, FGFR2, FGFR4, FGG, Fibrinogen, Fibroblast growth factor 15 (FGF15), Fibronectin, FLT1, FLT4, FN1, Follistatin, FSH, FSHR, Gastrin, GASTRIN, GCGR, GH (GROWTH HORMONE), GHR, Ghrelin, GHRH, GHRL, GIP, GLP-1, GLP-2, GLP1, GLP2, Glucagon, GLUCAGON, GLUT4, HCG, HEG1, Hepatic lipase, HGF, Histamine, HLA-DPB, HLA-DPB1, HMGB1, HSPG2, Hydrogen sulfide, ICAM1, ICOSLG, IFNA, IFNAR1, IFNAR2, IFNB, IFNG, IFNGR1, IFNGR2, IGF1, IGF1R, IGF2, IGF2R, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, IGHG4, IGLC1, IGLC7, IGLL5, IL-10, IL-12, IL-17A, IL-18, IL-1A, IL-1B, IL-22, IL-6, IL-8, IL10, IL10RA, IL10RB, IL12RB1, IL12RB2, IL17A, IL17RA, IL17RC, IL18R1, IL18RAP, ILIA, IL1B, IL1R1, IL1R2, IL22, IL22RA1, IL6, IL6R, INS, INSR, Insulin, Insulin-like growth factor 1 (IGF1), INSULIN-LIKE GROWTH FACTOR 1 (IGF1), INSULIN-LIKE GROWTH FACTOR 2 (IGF2), Irisin, ITGA1, ITGA2, ITGA3, ITGA4, 301645057.1ITGA5, ITGA6, ITGAM / CDllb, ITGAV, ITGAX / CDllc, ITGB1, ITGB2, ITGB2 / CD18, ITGB3, ITGB4, ITGB5, Kallidin, KDR, KLB, Lactoferrin, LAMA1, LAMA4, LAMA5, LAMB1, LAMB 2, LAMC1, Laminin, LAMININ, LBP, LDLR, LECT2, LEP, LEPR, Leptin, LEPTIN, Leukotriene B4, Leukotriene C4, Leukotriene D4, Leukotriene E4, LH, LHR, Lipocalin-2, Lipoprotein lipase, Lipoxin A4, Lipoxin B4, LPS-binding protein, LTBP1, LY86 / MD-1, LY96, LY96 / MD-2, Lysophosphatidic acid, Lysozyme, Mannose-binding lectin, Maresin 1, MASP2, Melatonin, MELATONIN, MMP1, MMP12, MMP14, MMP2, MMP3, MMP7, MMP8, MMP9, Motilin, MOTILIN, MSR1 / SR-A1, MUC1, MUC2, MUC5AC, Myostatin (GDF8), Neuropeptide Y, NIDI, NID2, Nitric oxide, Nitric oxide synthase (eNOS), Norepinephrine, NOTCH3, NPR 1, NPR 2, NPR 3, NR3C1 (GLUCOCORTICOID RECEPTOR), NR3C2 (MINERALOCORTICOID RECEPTOR), Omentin, OPG, Osteocalcin, OXTR, Oxyntomodulin, OXYTOCIN, P2RX7, PALI, Pancreatic polypeptide, Parathyroid hormone, PDCD1LG2, PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFRA, PDGFRB, PECAM1, Pentraxins PTX3, Perlecan, Peroxynitrite, Plasminogen, Platelet- activating factor (PAF), PLG, POSTN, PRLR, PROLACTIN, Properdin, PROS1, Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), Prostaglandin F2a (PGF2a), Protectin DI, PTH, PTH1R, PTHRP, PTX3, PYY, RANKL, RBP4, Reactive oxygen species, RENIN, Resistin, Resolvin DI, Resolvin D2, Resolvin El, RETINOL-BINDING PROTEIN 4, RP105 / TLR5L, S100A1, S100A6, S100A7, S100A8, S100A9, SCARB1, Sclerostin, SCUBE1, Secretin, SECRETIN, Secretory IgA, SELE, Selenoprotein P, SELP, Serotonin, SERPINE1, Serum amyloid A, SIGLEC1, SIGLEC10, SIGLEC14, SIGLEC7, SIGLEC9, SIRT1, Somatostatin, SOMATOSTATIN, SPARC, Sphingosine- 1 -phosphate, SPP1, SSTR2, Substance P, TESTOSTERONE, TGF-beta, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, THBS3, Thrombin, Thromboxane A2, THYROGLOBULIN, THYROID PEROXIDASE, Thyroxine (T4), THYROXINE (T4), TLL1, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TNC, TNF, TNFRSF1A, TNFRSF1B, TPO, Transferrin, TRANSTHYRETIN, TREM1, TREM2, Triiodothyronine (T3), TRIIODOTHYRONINE (T3), TSHR, UDP, UTP, Vasoactive intestinal peptide, VASOPRESSIN (A VP), VCAM1, VCAN, VDR, VEGFA, VEGFB, VEGFC, VEGFD, Visfatin, VITAMIN D (CALCITRIOL), VITAMIN D BINDING PROTEIN (GC), VLDLR, VTCN1 / B7-H4, and / or VWF. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for cardiovascular disease additionally comprises one or more appended domains. In embodiments an example appended domain is Apelin-13.301645057.17. Wound Healing

[0220] In embodiments, the cellular reprogramming protein modulates the immune processes of wound healing. In embodiments, the wound healing is selected from the group consisting of: acute wound healing, chronic wound healing, diabetic wound healing, impaired wound healing, delayed wound closure, severe bums, excessive inflammation, insufficient inflammation, defective re-epithelialization, impaired angiogenesis, excessive fibrosis or scarring, aberrant extracellular matrix deposition, sterile or infected wounds, and biofilm-associated wounds

[0221] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent wound healing. In embodiments, the FC domain of the cellular reprogramming protein for wound healing comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprises ACAN, ADAMIO, ADAM17, ADAMTS1, ADAMTS4, Adenosine, ADGRE3, Adiponectin, ADORA2A, ADP, Adrenomedullin, AGER, AGER (RAGE), AGER / RAGE, Agouti signaling protein (ASIP), Albumin, Aldosterone, Alpha-MSH (POMC-derived), AMP, Amylin, Amylin (IAPP), Angiopoietin-like 3 (ANGPTL3), ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANGPTL6, ANGPTL8, Apelin, Apolipoprotein A-I, Apolipoprotein B, Apolipoprotein C-III, Apolipoprotein E, AREG, ATP, BDNF, Beta-defensin 1 (hBDl), Beta-defensin 2 (hBD2), Beta-defensin 3 (hBD3), BGLAP, BGN, Biglycan, Bile acids, BMP2, BMP4, BMP6, BMP7, Bradykinin, BTC, C-reactive protein, Cl, Clq, Clr, Cis, C2, C3, C3a, C3aRl, C4, C5, C5a, C5aRl / CD88, C5aR2, C6, C7, C8, C9, CALCITONIN, Calcitonin gene-related peptide (CGRP), cAMP, Carbon monoxide, Cathelicidin LL-37, CCBE1, CCL1, CCL10, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL2, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CD14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform, CD36, CD44, CD80, CD86, Ceramide, cGMP, Chemerin, Cholecystokinin, Claudin-1 (CLDN1), CLEC4E (MINCLE), CLEC4E / MINCLE, CLEC6A (Dectin-2), CLEC6A / Dectin-2, CLEC7A (Dectin-1), CLEC7A / Dectin-1, COL11A1, COL12A1, COL14A1, COL15A1, COL18A1, COL1A1, COL1A2, COL3A1, COL4A1, 301645057.1COL4A2, COL5A1, COL6A1, Collagen 1, Collagen 10, Collagen 11, Collagen 12, Collagen 13, Collagen 14, Collagen 15, Collagen 16, Collagen 17, Collagen 18, Collagen 19, Collagen 2, Collagen 20, Collagen 21, Collagen 22, Collagen 23, Collagen 24, Collagen 25, Collagen 26, Collagen 27, Collagen 28, Collagen 3, Collagen 4, Collagen 5, Collagen 6, Collagen 7, Collagen 8, Collagen 9, Collagen I, Collagen III, Collagen V, Collagen VI, Collagen VII, Collagen XII, Collagen XIV, Collagen XVII (BP180), COMP, Corneodesmosin (CDSN), Corticotropin-releasing hormone (CRH), Cortisol, CR1 / CD35, CR2 / CD21, CRP, CSF1, CSF1R, CTSK, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, DCN, Decorin, Defensin alpha, Defensin beta, Desmocollin 1 (DSC1), Desmocollin 3 (DSC3), Desmoglein 1 (DSG1), Desmoglein 3 (DSG3), DKK 1, Dopamine, E-cadherin (CDH1), EDN1, EFEMP2, EGF, EGFR, Elafin (PI3), Elastin, EMILIN1, EMILIN2, Endocannabinoid 2-AG, Endocannabinoid anandamide, Endothelin-1, Endothelin-1 (EDN1), Epinephrine, ERBB2, ERBB3, ERBB4, EREG, F10, Fll, F12, F2, F2R / PAR1, F2RL1 / PAR2, F3, F5, F7, F8, F9, Factor B, Factor D, FBN3, FCAR / CD89, FCGR1A / CD64, FCGR2A / CD32, FCGR3A / CD16a, FCGR3B / CD16b, Fetuin-A, Fetuin-B, FGA, FGB, FGF1, FGF10, FGF11, FGF12, FGF13, FGF14, FGF15, FGF16, FGF17, FGF18, FGF19, FGF2, FGF20, FGF21, FGF22, FGF23, FGF3, FGF4, FGF5, FGF6, FGF7, FGF7 (KGF), FGF8, FGF9, FGFR1, FGFR2, FGFR3, FGFR4, FGG, Fibrillin-1, Fibrillin-2, Fibrinogen, Fibroblast growth factor 15 (FGF15), Fibronectin, Fibulin-2, Fibulin-5, Filaggrin-processed NMF (contextual), FLT1 (VEGFR1), FLT4 (VEGFR3), FN1, Follistatin, Gastrin, GCGR, GDF5, GH, Ghrelin, GIP, GLP-1, GLP-2, Glucagon, GLUT4, HBEGF, Hepatic lipase, HGF, Histamine, HLA-DPB, HLA-DPB1, HMGB1, HSPG2, HYALURONAN, Hydrogen sulfide, IBSP, ICAM1, ICOSLG, IFNA, IFNAR1, IFNAR2, IFNB, IFNG, IFNGR1, IFNGR2, IGF1, IGF1R, IGF2, IGHG4, IGLC1, IGLC7, IGLL5, IHH, IL-1, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-17A, IL-17F, IL-18, IL-19, IL-1A, IL-1B, IL-2, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL- 3, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL10, IL10RA, IL10RB, IL12RB1, IL12RB2, IL15, IL17A, IL17RA, IL17RC, IL18R1, IL18RAP, ILIA, IL1B, IL1R1, IL1R2, IL22, IL22RA1, IL33R (ST2 / IL1RL1), IL6, IL6R, IL7, INS, INSR, Insulin, Insulin-like growth factor 1 (IGF1), Integrin alpha3 (ITGA3), Integrin alpha6 (ITGA6), Integrin betal (ITGB1), Integrin beta4 (ITGB4), Irisin, ITGA1, ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGA9, ITGAM / CDllb, ITGAV, ITGAX / CDllc, ITGB1, ITGB2 / CD18, ITGB3, ITGB5, ITGB7, ITGB8, Kallidin, Kallikrein KLK14, Kallikrein KLK5, 301645057.1Kallikrein KLK7, KDR (VEGFR2), KITLG (SCF), KLB, KLOTHO, Lactoferrin, LAMA2, LAMA4, LAMA5, LAMB1, LAMC1, Laminin, Laminin-332, Laminin-511, Laminin-521, LBP, LDLR, LECT2, LEKTI (SPINK5), LEPR, Leptin, Leukotriene B4, Leukotriene C4, Leukotriene D4, Leukotriene E4, Lipocalin-2, Lipoprotein lipase, Lipoxin A4, Lipoxin B4, LPS-binding protein, LTA, LTB, LTBP1, LTBP2, LTBP4, LUB RICIN, Lumican, LY86 / MD-1, LY96 (MD-2), LY96 / MD-2, Lysophosphatidic acid, Lysozyme, LYVE1, MADCAM1, Mannose-binding lectin, Maresin 1, MASP2, MATN1, MATN3, Melatonin, MMP1, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP18, MMP19, MMP2, MMP20, MMP21, MMP22, MMP23, MMP24, MMP25, MMP26, MMP27, MMP28, MMP3, MMP4, MMP5, MMP6, MMP7, MMP8, MMP9, Motilin, MSR1 / SR-A1, MUC1, MUC16, MUC2, MUC4, MUC5AC, Myostatin (GDF8), N-cadherin (CDH2), NELLI, Neuropeptide Y, NIDI, NID2, Nidogen-1, Nidogen-2, Nitric oxide, Norepinephrine, Occludin (OCLN), Omentin, OPG, Osteocalcin, Osteopontin, Oxyntomodulin, P2RX7, PALI, Pancreatic polypeptide, Parathyroid hormone, PDCD1LG2, PDCD1LG2 (PD-L2), PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFC, PDGFD, PDGFRA, PDGFRB, PDPN (Podoplanin), PECAM1, Pentraxins PTX3, Periostin, Perlecan, Peroxynitrite, Plasminogen, Platelet-activating factor (PAF), PLG, POSTN, PRG4, Properdin, Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), Prostaglandin F2a (PGF2a), Protectin DI, PTH, PTH1R, PTX3, PYY, RANKL, RBP4, Reactive oxygen species, RELN, Resistin, Resolvin DI, Resolvin D2, Resolvin El, RP105 / TLR5L, RSPO1, RSPO2, RSPO3, S100A1, S100A6, S100A7, S100A7 (Psoriasin), S100A8, S100A9, SCARB1, Sclerostin, Secretin, Secretory IgA, SELE, SELE (E-selectin), Selenoprotein P, SELP, SELP (P-selectin), Serotonin, SERPINE1, Serum amyloid A, SHH, SIGLEC1, SIGLEC10, SIGLEC14, SIGLEC7, SIGLEC9, SIRT1, SLPI, Somatostatin, SOST, SPARC, Sphingosine- 1 -phosphate, SPON1, SPP1, SSTR2, Substance P, Tenascin-C, Tenascin-X, TGF-beta, TGF-betal (TGFB1), TGF-beta2 (TGFB2), TGF-beta3 (TGFB3), TGFA, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, THBS3, Thrombin, Thrombospondin- 1, Thrombospondin-2, Thromboxane A2, Thyroxine (T4), TIE2, TIMP1, TIMP2, TIMP3, TIMP4, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TNC, TNF, TNFRSF11A (RANK), TNFRSF11B (OPG), TNFRSF1A, TNFRSF1B, TNFSF10, TNFSF11, TNFSF11 (RANKL), TNFSF12, TNFSF13, TNFSF14, TNFSF15, TNFSF4, TNFSF8, TNFSF9, TPO, Transferrin, TREM1, TREM2, Triiodothyronine (T3), TSLP, TSLP receptor (TSLPR / CRLF2), UDP, UTP, Vasoactive intestinal peptide, VCAM1, VCAN, VEGFA, VEGFB, VEGFC, VEGFD, VEGFR2 (KDR), VEGFR3 (FLT4), Versican, Visfatin, VITAMIN D (CALCITRIOL), Vitronectin, VLDLR, VTCN1 (B7-H4), VTCN1 / B7- 301645057.1H4, VWF, WNT10A, WNT10B, WNT3A, and / or WNT5A. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for wound healing additionally comprises one or more appended domains. In embodiments the appended protein is the KPV protein.8. Respiratory Disease

[0222] In embodiments, the cellular reprogramming protein modulates the immune processes of respiratory disease. In embodiments, the respiratory disease is selected from the group consisting of: acute and chronic airway inflammation; infectious and post-infectious respiratory conditions; obstructive lung diseases; interstitial and fibrotic lung disease; vascular or thrombo-inflammatory lung disease; and immune-mediated or dysregulated repair processes of the upper or lower respiratory tract.

[0223] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent respiratory disease. In embodiments, the FC domain of the cellular reprogramming protein for respiratory disease comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprises ADAMIO, ADAM17, ADAMTS1, ADAMTS4, Adenosine, ADGRE3, ADIPOQ, ADORA2A, ADP, AGER, AGER / RAGE, AGTR1, AGTR2, AMP, ANGIOTENSIN II, ANGPT1, ANGPT2, ANP (NPPA), AREG, ATP, BGN, BMP2, BMP4, BMP7, BNP (NPPB), BPIFA1, Bradykinin, C-reactive protein, Cl, Clq, Clr, Cis, C2, C3, C3a, C3aRl, C3AR1, C4, C5, C5a, C5AR1, C5aRl / CD88, C5aR2, C6, C7, C8, C9, Calcitonin gene-related peptide (CGRP), cAMP, Carbon monoxide, Cathelicidin LL-37, CCL11, CCL17, CCL19, CCL2, CCL20, CCL21, CCL3, CCL4, CCL5, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CD14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform, CD36, CD44, CD80, CD86, Ceramide, cGMP, CLEC4E, CLEC4E / MINCLE, CLEC6A, CLEC6A / Dectin-2, CLEC7A, CLEC7A / Dectin-1, COL18A1, COL1A1, COL1A2, COL3A1, COL4A1, COL4A2, COL5A1, COL6A1, COL6A2, COL7A1, Collagen I, Collagen III, Collagen IV, Corticotropin-releasing hormone (CRH), CR1 / CD35, CR2 / CD21, CRELD1, CRP, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL2, CXCL8, CXCL9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5,301645057.1CXCR6, DCN, Defensin alpha, Defensin beta, Dopamine, EDN1, EDNRA, EDNRB, EGF, ELN, Endocannabinoid 2-AG, Endocannabinoid anandamide, Endothelin-1, Epinephrine, F2R / PAR1, F2RL1 / PAR2, Factor B, Factor D, FBN1, FCAR / CD89, FCGR1A / CD64, FCGR2A / CD32, FCGR3A / CD16a, FCGR3B / CD16b, FGA, FGB, FGF10, FGF19, FGF2, FGF21, FGF7, FGFR1, FGFR2, FGFR4, FGG, Fibrinogen, Fibronectin, FLT1, FLT4, FN1, GHRL, HBEGF, HEG1, Histamine, HLA-DPB, HLA-DPB1, HMGB1, HSPG2, Hydrogen sulfide, ICAM1, ICOSLG, IFNA, IFNAR1, IFNAR2, IFNB, IFNG, IFNGR1, IFNGR2, IGF1, IGHG4, IGLC1, IGLC7, IGLL5, IL-10, IL-12, IL-17A, IL-18, IL-1A, IL-1B, IL-22, IL-6, IL-8, IL10, IL10RA, IL10RB, IL12RB1, IL12RB2, IL13, IL13RA1, IL17A, IL17RA, IL17RC, IL18R1, IL18RAP, ILIA, IL1B, IL1R1, IL1R2, IL1RL1 (ST2), IL22, IL22RA1, IL25, IL33, IL6, IL6R, IL8, INS, ITGA1, ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGAM / CDllb, ITGAV, ITGAX / CDllc, ITGB1, ITGB2, ITGB2 / CD18, ITGB3, ITGB4, ITGB5, ITGB6, ITGB8, Kallidin, KDR, Lactoferrin, LAMA1, LAMA3, LAMA4, LAMA5, LAMB1, LAMB2, LAMC1, Laminin, LBP, LEP, Leukotriene B4, Leukotriene C4, Leukotriene D4, Leukotriene E4, Lipoxin A4, Lipoxin B4, LPS-binding protein, LTBP1, LY86 / MD-1, LY96, LY96 / MD-2, Lysophosphatidic acid, Lysozyme, MADCAM1, Mannose-binding lectin, Maresin 1, MASP2, Melatonin, MMP1, MMP12, MMP14, MMP2, MMP3, MMP7, MMP8, MMP9, MSR1 / SR-Al, MUC1, MUC16, MUC2, MUC5AC, MUC5B, Neuropeptide Y, NIDI, NID2, Nitric oxide, Nitric oxide synthase (eNOS), NODI, NOD2, Norepinephrine, NOTCH3, NPR 1, NPR 2, NPR 3, P2RX7, PALI, PDCD1LG2, PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFRA, PDGFRB, PECAM1, Pentraxins PTX3, Perlecan, Peroxynitrite, Plasminogen, Plateletactivating factor (PAF), PLG, POSTN, Properdin, PROS1, Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), Prostaglandin F2a (PGF2a), Protectin DI, PTX3, Reactive oxygen species, Resolvin DI, Resolvin D2, Resolvin El, RP105 / TLR5L, RSPO1, RSPO3, S100A1, S100A6, S100A7, S100A8, S100A9, SCGB1A1, SCUBE1, Secretory IgA, SELE, SELP, Serotonin, SERPINE1, Serum amyloid A, SFTPA1, SFTPA2, SFTPB, SFTPC, SFTPD, SHH, SIGLEC1, SIGLEC10, SIGLEC14, SIGLEC7, SIGLEC9, Somatostatin, SPARC, Sphingosine- 1 -phosphate, SPP1, Substance P, TGFA, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, THBS3, Thrombin, Thromboxane A2, TLL1, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TNC, TNF, TNFRSF1A, TNFRSF1B, TREM1, TREM2, UDP, UTP, Vasoactive intestinal peptide, VCAM1, VC AN, VEGFA, VEGFB, VEGFC, VEGFD, VTCN1, VTCN1 / B7-H4, VWF, WNT3A, and / or WNT5A. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming301645057.1protein for respiratory disease additionally comprises one or more appended domains. In embodiments the appended domain is VIP.9. Urinary and Excretory System Disorders

[0224] In embodiments, the cellular reprogramming protein modulates the immune processes of urinary and excretory system disorders. In embodiments, the urinary and excretory system disorders is selected from the group consisting of: infectious and post-infectious conditions of the kidney and urinary tract; autoimmune and inflammatory nephritides; obstructive, ischemic, or toxic injuries; interstitial and tubulointerstitial diseases; glomerular diseases; lower urinary tract inflammatory conditions; urothelial barrier dysfunction; nephrolithiasis with inflammatory sequelae; transplant-related immune injury; and systemic disorders with renal and / or urothelial inflammatory involvement.

[0225] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent urinary and / or excretory system disorders. In embodiments, the FC domain of the cellular reprogramming protein for urinary and excretory system disorders comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprises ADAM 10, ADAM17, ADAMTS1, ADAMTS4, Adenosine, ADGRE3, ADIPOQ, ADORA2A, ADP, AGER, AGER / RAGE, AGRIN, AGTR1, AGTR2, ALDOSTERONE, AMP, ANGIOTENSIN II, ANGIOTENSINOGEN, ANGPT1, ANGPT2, ANP (NPPA), ATP, AVPR1A, AVPR2, BGN, BMP2, BMP4, BMP7, BNP (NPPB), Bradykinin, C-reactive protein, Cl, Clq, Clr, Cis, C2, C3, C3a, C3aRl, C3AR1, C4, C5, C5a, C5AR1, C5aRl / CD88, C5aR2, C6, C7, C8, C9, Calcitonin gene-related peptide (CGRP), cAMP, Carbon monoxide, Cathelicidin LL-37, CCL19, CCL2, CCL20, CCL21, CCL3, CCL4, CCL5, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CD14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform, CD36, CD44, CD80, CD86, Ceramide, cGMP, CLEC4E / MINCLE, CLEC6A / Dectin-2, CLEC7A / Dectin-1, COL18A1, COL1A1, COL1A2, COL3A1, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL5A1, COL6A1, COL6A2, COL7A1, Collagen I, Collagen III, Collagen IV, Corticotropin-releasing hormone (CRH), CR1 / CD35, CR2 / CD21, CRELD1, CRP, CXCL1, CXCL10, CXCL11, CXCL12, CXCL2, CXCL8, CXCL9, CXCR1,301645057.1CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, DCN, Defensin alpha, Defensin beta, Dopamine, EDN1, EDNRA, EDNRB, Endocannabinoid 2- AG, Endocannabinoid anandamide, Endothelin-1, Epinephrine, ERYTHROPOIETIN (EPO), F2R / PAR1, F2RL1 / PAR2, Factor B, Factor D, FCAR / CD89, FCGR1A / CD64, FCGR2A / CD32, FCGR3A / CD16a, FCGR3B / CD16b, FGA, FGB, FGF10, FGF19, FGF2, FGF21, FGF23, FGF7, FGFR1, FGFR2, FGFR3, FGFR4, FGG, Fibrinogen, Fibronectin, FLT1, FLT4, FN1, GHRL, HEG1, Histamine, HLA-DPB, HLA-DPB1, HMGB1, HSPG2, Hydrogen sulfide, ICAM1, ICOSLG, IFNA, IFNAR1, IFNAR2, IFNB, IFNG, IFNGR1, IFNGR2, IGF1, IGHG4, IGLC1, IGLC7, IGLL5, IL-10, IL-12, IL-17A, IL-18, IL-1A, IL-1B, IL-22, IL-6, IL-8, IL10, IL10RA, IL10RB, IL12RB1, IL12RB2, IL17A, IL17RA, IL17RC, IL18R1, IL18RAP, ILIA, IL1B, IL1R1, IL1R2, IL22, IL22RA1, IL6, IL6R, INS, ITGA1, ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGAM / CDllb, ITGAV, ITGAX / CDllc, ITGB1, ITGB2, ITGB2 / CD18, ITGB3, ITGB4, ITGB5, Kallidin, KDR, KLB, KLOTHO, Lactoferrin, LAMA1, LAMA4, LAMA5, LAMB1, LAMB2, LAMC1, Laminin, LBP, LEP, Leukotriene B4, Leukotriene C4, Leukotriene D4, Leukotriene E4, Lipoxin A4, Lipoxin B4, LPS-binding protein, LTBP1, LY86 / MD-1, LY96, LY96 / MD-2, Lysophosphatidic acid, Lysozyme, Mannose-binding lectin, Maresin 1, MASP2, Melatonin, MMP1, MMP12, MMP14, MMP2, MMP3, MMP7, MMP8, MMP9, MSR1 / SR-Al, MUC1, MUC2, MUC5AC, Neuropeptide Y, NIDI, NID2, Nitric oxide, Nitric oxide synthase (eNOS), NODI, NOD2, Norepinephrine, NOTCH3, NPR 1, NPR 2, NPR 3, P2RX7, PALI, PDCD1LG2, PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFRA, PDGFRB, PECAM1, Pentraxins PTX3, Perlecan, Peroxynitrite, Plasminogen, Platelet- activating factor (PAF), PLG, POSTN, Properdin, PROS1, Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), Prostaglandin F2a (PGF2a), Protectin DI, PTH, PTH1R, PTX3, Reactive oxygen species, RENIN, Resolvin DI, Resolvin D2, Resolvin El, RP105 / TLR5L, S100A1, S100A6, S100A7, S100A8, S100A9, SCUBE1, Secretory IgA, SELE, SELP, Serotonin, SERPINE1, Serum amyloid A, SHH, SIGLEC1, SIGLEC10, SIGLEC14, SIGLEC7, SIGLEC9, Somatostatin, SPARC, Sphingosine- 1 -phosphate, SPP1, Substance P, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, THBS3, Thrombin, Thromboxane A2, TLL1, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TNC, TNF, TNFRSF1A, TNFRSF1B, TREM1, TREM2, UDP, UMOD, UTP, Vasoactive intestinal peptide, VASOPRESSIN (A VP), VCAM1, VCAN, VEGFA, VEGFB, VEGFC, VEGFD, VITAMIN D (CALCITRIOL), VTCN1 / B7-H4, VWF, WNT4, and / or WNT7B. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for urinary and excretory system disorders301645057.1additionally comprises one or more appended domains. In embodiments the appended protein is uroguanylin protein or a fragment thereof.10. Infertility

[0226] In embodiments, the cellular reprogramming protein modulates the immune processes of infertility. In embodiments, the infertility is selected from the group consisting of: female infertility, male infertility, combined infertility, unexplained infertility, implantation failure, recurrent pregnancy loss, ovarian or testicular dysfunction with immune features, gamete or embryo quality impairment, endometrial receptivity disorders, uterine or tubal inflammation, and reproductive-tract immune dysregulation.

[0227] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent infertility. In embodiments, the FC domain of the cellular reprogramming protein for infertility comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprises ACTH (POMC), ACTIVIN A, ACTIVIN B, ADAM10, ADAM17, ADAMTS1, ADAMTS4, ADIPONECTIN, ADIPOQ, AGER, Agrin, ALBUMIN, ALDOSTERONE, AMH, AMHR2, AMYLA°N (IAPP), ANGIOTENSIN II, ANGIOTENSINOGEN, ANGPT1, ANGPT2, ANP (NPPA), ANTI-MULLERIAN HORMONE (AMH), AR, AREG, AVPR1A, AVPR2, BGN, Biglycan, BMP2, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BNP (NPPB), C3, C5, CALCITONIN, CBG (SERPINA6), CCBE1, CCL11, CCL19, CCL2, CCL21, CCL5, CCR2, CCR5, CCR7, CD14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform, CD44, CD80, CD86, CHROMOGRANIN A, COL18A1, COL1A1, COL3A1, COL4A1, COL4A2, COL5A1, COL6A1, COL7A1, Collagen I, Collagen II, Collagen III, Collagen IV, Collagen V, Collagen VI, CORTISOL, CSF1, CTSB, CTSD, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL2, CXCL3, CXCL8, CXCL9, CXCR3, CXCR4, CXCR5, DCN, Decorin, Delta-like 1, Delta-like 4, DHEA, DHH, DLL4, EGF, EGFR, ELN, EMILIN 1, EMILIN2, EPO, ERBB2, ESRI, ESR2, ESTRADIOL, FGF1, FGF10, FGF18, FGF19, FGF2, FGF20, FGF21, FGF23, FGF4, FGF5, FGF7, FGF8, FGF9, FGFR1, FGFR2, FGFR4, Fibronectin, FLT1, FLT1 (VEGFR1), FLT4 (VEGFR3), FN1, FSH, FSHR, GAL1 / LGALS1,301645057.1GAL3 / LGALS3, GASTRIN, GCGR, GH (GROWTH HORMONE), GHR, GHRH, GHRL, GIP, GLP1, GLP2, GLUCAGON, GNRHR, HBEGF, HCG, HLA-G, HSPG2, HYALURONAN, ICAM1, ICOSLG, IFNG, IGF1, IGF1R, IGF2, IGF2R, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, IHH, IL-10, IL-11, IL-1A, IL-1B, IL-6, IL10, IL10RA, IL15, IL17A, ILIA, IL1B, IL1R1, IL1R2, IL22, IL22RA1, IL6, IL6R, IL7, IL8, INHIBIN A, INHIBIN B, INS, INSR, INSULIN-LIKE GROWTH FACTOR 1 (IGF1), INSULIN-LIKE GROWTH FACTOR 2 (IGF2), ITGA1, ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGA9, ITGAE, ITGAV, ITGB1, ITGB3, ITGB4, ITGB5, ITGB7, ITGB8, IZUMO1, Jaggedl, Jagged2, JUNO, KDR, KDR (VEGFR2), KISS1R, KISSPEPTIN, KLB, LAMA3, LAMA4, LAMA5, LAMB1, LAMC1, Laminin, LAMININ, LEP, LEPR, LEPTIN, LGALS1, LGALS3, LH, LHR, LIF, Lumican, LY96, LYVE1, MADCAM1, MELATONIN, MMP1, MMP10, MMP11, MMP12, MMP13, MMP14, MMP16, MMP2, MMP3, MMP4, MMP5, MMP6, MMP7, MMP8, MMP9, MOTILIN, MUC1, MUC16, NIDI, NID2, Nidogen, NR3C1 (GLUCOCORTICOID RECEPTOR), NR3C2 (MINERALOCORTICOID RECEPTOR), OXTR, OXytocin, OXYTOCIN, PDCD1LG2, PDCD1LG2 (PD-L2), PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFRA, PDGFRB, PDPN (Podoplanin), PECAM1, Perlecan, PGR, PLG, POSTN, PRLR, PROGESTERONE, PROLACTIN, PTH, PTH1R, PTHRP, PYY, RELAXIN, RELN, RENIN, RETINOL-BINDING PROTEIN 4, RSPO1, RSPO2, RSPO3, RSPO4, S100A8, S100A9, SECRETIN, SELE, SELP, SERPINE1, SHH, SOMATOSTATIN, SPARC, SPON1, SPP1, Tenascin-C, TESTOSTERONE, TGFA, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, THYROGLOBULIN, THYROID PEROXIDASE, THYROXINE (T4), TIE2, TLR2, TLR4, TLR9, TNC, TNF, TNFRSF1A, TNFRSF1B, TRANSTHYRETIN, TRIIODOTHYRONINE (T3), TSHR, VASOPRESSIN (A VP), VCAM1, VCAN, VDR, VEGFA, VEGFB, VEGFC, VEGFD, VITAMIN D (CALCITRIOL), VITAMIN D BINDING PROTEIN (GC), Vitronectin, VTCN1, VTCN1 (B7-H4), WNT1, WNT10A, WNT10B, WNT11, WNT16, WNT2, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, ZP3, and / or ZP4. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for infertility additionally comprises one or more appended domains. In example embodiments the appended protein is Kisspeptin 10.11. Osteoporosis and Fracture

[0228] In embodiments, the cellular reprogramming protein modulates the immune processes of osteoporosis and fracture. In embodiments, the osteoporosis and fracture is 301645057.1selected from the group consisting of: primary osteoporosis, secondary osteoporosis, low bone mineral density, osteopenia, fragility fractures, delayed union, non-union, malunion, impaired callus formation, and dysregulated bone remodeling with inflammatory features

[0229] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent osteoporosis and / or fractures. In embodiments, the FC domain of the cellular reprogramming protein for osteoporosis and fracture comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprises AC AN, ACTH (POMC), ADAM 10, ADAM17, ADAMTS1, ADAMTS4, Adenosine, ADGRE3, Adiponectin, ADIPONECTIN, ADIPOQ, ADORA2A, ADP, Adrenomedullin, AGER, AGER / RAGE, Agrin, Albumin, ALBUMIN, Aldosterone, ALDOSTERONE, AMH, AMP, Amylin, Amylin (IAPP), AMYLA°N (IAPP), Angiopoietin-like 3 (ANGPTL3), ANGIOTENSIN II, ANGIOTENSINOGEN, ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANGPTL6, ANGPTL8, ANP (NPPA), Apelin, Apolipoprotein A-I, Apolipoprotein B, Apolipoprotein C-III, Apolipoprotein E, AR, AREG, ATP, AVPR1A, AVPR2, BDNF, BGLAP, BGN, Biglycan, Bile acids, BMP2, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BNP (NPPB), Bradykinin, BTC, C-reactive protein, Cl, Clq, Clr, Cis, C2, C3, C3a, C3aRl, C4, C5, C5a, C5aRl / CD88, C5aR2, C6, C7, C8, C9, CALCITONIN, Calcitonin gene-related peptide (CGRP), cAMP, Carbon monoxide, Cathelicidin LL-37, CBG (SERPINA6), CCL1, CCL10, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL2, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CD14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform, CD36, CD80, CD86, Ceramide, cGMP, Chemerin, Cholecystokinin, CHROMOGRANIN A, CLEC4E / MINCLE, CLEC6A / Dectin-2, CLEC7A / Dectin-1, COL11A1, COL12A1, COL14A1, COL15A1, COL18A1, COL1A1, COL1A2, COL3A1, COL4A1, COL5A1, Collagen 1, Collagen 10, Collagen 11, Collagen 12, Collagen 13, Collagen 14, Collagen 15, Collagen 16, Collagen 17, Collagen 18, Collagen 19, Collagen 2, Collagen 20, Collagen 21, Collagen 22, Collagen 23, Collagen 24, Collagen 25, Collagen 26, Collagen 27, Collagen 28, Collagen 3, Collagen 4, Collagen 5, Collagen 6, Collagen 7, Collagen 8, Collagen 9, Collagen I, Collagen II, Collagen301645057.1III, Collagen IV, Collagen V, Collagen VI, COMP, Corticotropin-releasing hormone (CRH), Cortisol, CORTISOL, CR1 / CD35, CR2 / CD21, CRP, CSF1, CSF1R, CTSK, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, DCN, Decorin, Defensin alpha, Defensin beta, Delta-like 1, Deltalike 4, DHEA, DHH, DKK 1, DLL4, Dopamine, EDN1, EGF, Endocannabinoid 2- AG, Endocannabinoid anandamide, Endothelin-1, Epinephrine, EPO, EREG, ESRI, ESR2, F10, Fl 1, F12, F2, F2R / PAR1, F2RL1 / PAR2, F3, F5, F7, F8, F9, Factor B, Factor D, FCAR / CD89, FCGR1A / CD64, FCGR2A / CD32, FCGR3A / CD16a, FCGR3B / CD16b, Fetuin-A, Fetuin-B, FGA, FGB, FGF1, FGF10, FGF11, FGF12, FGF13, FGF14, FGF15, FGF16, FGF17, FGF18, FGF19, FGF2, FGF20, FGF21, FGF22, FGF23, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, FGFR1, FGFR4, FGG, Fibrinogen, Fibroblast growth factor 15 (FGF15), Fibronectin, FN1, Follistatin, FSH, FSHR, GAL1 / LGALS1, GAL3 / LGALS3, Gastrin, GASTRIN, GCGR, GDF5, GH, GH (GROWTH HORMONE), GHR, Ghrelin, GHRH, GHRL, GIP, GLP-1, GLP-2, GLP1, GLP2, Glucagon, GLUCAGON, GLUT4, HBEGF, HCG, Hepatic lipase, HGF, Histamine, HLA-DPB, HLA-DPB1, HMGB1, HSPG2, Hydrogen sulfide, IBSP, ICAM1, ICOSLG, IFNA, IFNAR1, IFNAR2, IFNB, IFNG, IFNGR1, IFNGR2, IGF1, IGF1R, IGF2, IGF2R, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, IGHG4, IGLC1, IGLC7, IGLL5, IHH, IL-1, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-17A, IL-18, IL-19, IL-1A, IL-1B, IL-2, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-3, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL10, IL10RA, IL10RB, IL12RB1, IL12RB2, IL17A, IL17RA, IL17RC, IL18R1, IL18RAP, ILIA, IL1B, IL1R1, IL1R2, IL22, IL22RA1, IL6, IL6R, INS, INSR, Insulin, Insulin-like growth factor 1 (IGF1), INSULIN-LIKE GROWTH FACTOR 1 (IGF1), INSULIN-LIKE GROWTH FACTOR 2 (IGF2), Irisin, ITGA1, ITGA2, ITGA3, ITGA5, ITGA6, ITGAM / CDllb, ITGAV, ITGAX / CDllc, ITGB1, ITGB2 / CD18, ITGB3, ITGB5, ITGB8, Jaggedl, Jagged2, Kallidin, KLB, KLOTHO, Lactoferrin, LAMA2, LAMB1, LAMC1, Laminin, LAMININ, LBP, LDLR, LECT2, LEP, LEPR, Leptin, LEPTIN, Leukotriene B4, Leukotriene C4, Leukotriene D4, Leukotriene E4, LH, LHR, LIF, Lipocalin-2, Lipoprotein lipase, Lipoxin A4, Lipoxin B4, LPS-binding protein, LTA, LTB, LTBP1, LUBRICIN, Lumican, LY86 / MD-1, LY96 / MD-2, Lysophosphatidic acid, Lysozyme, Mannose-binding lectin, Maresin 1, MASP2, MATN1, MATN3, Melatonin, MELATONIN, MMP1, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP18, MMP19, MMP2, MMP20, MMP21, MMP22, MMP23, MMP24, MMP25, MMP26, MMP27, 301645057.1MMP28, MMP3, MMP4, MMP5, MMP6, MMP7, MMP8, MMP9, Motilin, MOTILIN, MSR1 / SR-A1, MUC1, MUC2, MUC5AC, Myostatin (GDF8), NELLI, Neuropeptide Y, NIDI, NID2, Nidogen, Nitric oxide, Norepinephrine, NR3C1 (GLUCOCORTICOID RECEPTOR), NR3C2 (MINERALOCORTICOID RECEPTOR), Omentin, OPG, Osteocalcin, Osteopontin, OXTR, Oxyntomodulin, OXYTOCIN, P2RX7, PALI, Pancreatic polypeptide, Parathyroid hormone, PDCD1LG2, PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFC, PDGFD, PECAM1, Pentraxins PTX3, Periostin, Perlecan, Peroxynitrite, Plasminogen, Plateletactivating factor (PAF), POSTN, PRG4, PRLR, PROLACTIN, Properdin, Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), Prostaglandin F2a (PGF2a), Protectin DI, PTH, PTH1R, PTHRP, PTX3, PYY, RANKL, RBP4, Reactive oxygen species, RENIN, Resistin, Resolvin DI, Resolvin D2, Resolvin El, RETINOL-BINDING PROTEIN 4, RP105 / TLR5L, RSPO1, RSPO2, RSPO3, RSPO4, S100A1, S100A6, S100A7, S100A8, S100A9, SCARB1, Sclerostin, Secretin, SECRETIN, Secretory IgA, SELE, Selenoprotein P, SELP, Serotonin, Serum amyloid A, SHH, SIGLEC1, SIGLEC10, SIGLEC14, SIGLEC7, SIGLEC9, SIRT1, Somatostatin, SOMATOSTATIN, SOST, SPARC, Sphingosine- 1 -phosphate, SPP1, SSTR2, Substance P, Tenascin-C, TESTOSTERONE, TGF-beta, TGFA, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS3, Thrombin, Thrombospondin- 1, Thrombospondin-2, Thromboxane A2, THYROGLOBULIN, THYROID PEROXIDASE, Thyroxine (T4), THYROXINE (T4), TIMP1, TIMP2, TIMP3, TIMP4, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TNF, TNFRSF11A (RANK), TNFRSF11B (OPG), TNFRSF1A, TNFRSF1B, TNFSF10, TNFSF11, TNFSF11 (RANKL), TNFSF12, TNFSF13, TNFSF14, TNFSF15, TNFSF4, TNFSF8, TNFSF9, TPO, Transferrin, TRANSTHYRETIN, TREM1, TREM2, Triiodothyronine (T3), TRIIODOTHYRONINE (T3), TSHR, UDP, UTP, Vasoactive intestinal peptide, VASOPRESSIN (A VP), VCAM1, VCAN, VDR, VEGFA, VEGFB, VEGFC, VEGFD, Versican, Visfatin, VITAMIN D (CALCITRIOL), VITAMIN D BINDING PROTEIN (GC), Vitronectin, VLDLR, VTCN1 / B7-H4, VWF, WNT1, WNT10A, WNT10B, WNT11, WNT16, WNT2, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, and / or WNT9B. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for osteoporosis and fracture additionally comprises one or more appended domains. In embodiments the appended protein is PTH(1-14).301645057.112. Hearing Loss

[0230] In embodiments, the cellular reprogramming protein modulates the immune processes of hearing loss. In embodiments, the hearing loss is selected from the group consisting of: sensorineural hearing loss, conductive hearing loss, mixed hearing loss, central auditory processing disorders with inflammatory features, acute or sudden hearing loss, progressive or chronic hearing loss, noise-induced hearing loss, ototoxicity-associated hearing loss, autoimmune-mediated inner ear disease, infection-associated hearing loss, age-related hearing loss, and cochlear synaptopathy.

[0231] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent hearing loss. In embodiments, the FC domain of the cellular reprogramming protein for hearing loss comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprise ADAMIO, ADAM17, ADAMTS1, ADAMTS4, Adenosine, ADGRE3, Adiponectin, ADORA2A, ADP, Adrenomedullin, AGER, AGER (RAGE), AGER / RAGE, Aggrecan, Agouti signaling protein (ASIP), Agrin, Albumin, Aldosterone, Alpha-MSH (POMC -derived), AMP, Amylin, Amylin (IAPP), Angiopoietin-like 3 (ANGPTL3), ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANGPTL6, ANGPTL8, Apelin, Apolipoprotein A-I, Apolipoprotein B, Apolipoprotein C-III, Apolipoprotein E, AREG, ARTN, ATP, BDNF, Beta-defensin 1 (hBDl), Beta-defensin 2 (hBD2), Beta-defensin 3 (hBD3), BGN, Biglycan, Bile acids, BMP2, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, Bradykinin, Brevican, BTC, C-reactive protein, Cl, Clq, Clr, Cis, C2, C3, C3a, C3aRl, C4, C5, C5a, C5aRl / CD88, C5aR2, C6, C7, C8, C9, Calcitonin gene-related peptide (CGRP), cAMP, Carbon monoxide, Cathelicidin LL-37, CCBE1, CCL17, CCL19, CCL2, CCL20, CCL21, CCL27, CCL28, CCL3, CCL4, CCL5, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CD 14, CD274 CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform, CD36, CD44, CD80, CD86, Ceramide, cGMP, Chemerin, Cholecystokinin, Claudin-1 (CLDN1), CLEC4E (MINCLE), CLEC4E / MINCLE, CLEC6A (Dectin-2), CLEC6A / Dectin-2, CLEC7A (Dectin-1), CLEC7A / Dectin-1, CLU, CNTF, COL18A1, COL1A1, COL3A1, COL4A1, COL4A2, COL5A1, COL6A1, Collagen I, Collagen II, Collagen III, Collagen IV, Collagen V, Collagen VI, Collagen VII, Collagen XII, Collagen 301645057.1XIV, Collagen XVII (BP180), Contactin-1, Contactin-2, Comeodesmosin (CDSN), Corticotropin-releasing hormone (CRH), Cortisol, CR1 / CD35, CR2 / CD21, CRB1, CRP, CX3CL1, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL2, CXCL3, CXCL8, CXCL9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, DCN, Decorin, Defensin alpha, Defensin beta, Delta-like 1, Delta-like 4, Desmocollin 1 (DSC1), Desmocollin 3 (DSC3), Desmoglein 1 (DSG1), Desmoglein 3 (DSG3), DHH, DKK 1, DLL4, Dopamine, E-cadherin (CDH1), EFEMP1, EFEMP2, EGF, EGFL8, EGFR, Elafin (PI3), Elastin, EMILIN1, EMILIN2, Endocannabinoid 2-AG, Endocannabinoid anandamide, Endothelin-1, Endothelin-1 (EDN1), Ephrin-Al, Ephrin-A2, Ephrin-A3, Ephrin-Bl, Ephrin-B2, Epinephrine, ERBB2, ERBB3, ERBB4, EREG, F2R / PAR1, F2RL1 / PAR2, Factor B, Factor D, FAT3, FBN3, FCAR / CD89, FCGR1A / CD64, FCGR2A / CD32, FCGR3A / CD16a, FCGR3B / CD16b, Fetuin-A, Fetuin-B, FGF1, FGF10, FGF18, FGF19, FGF2, FGF20, FGF21, FGF23, FGF4, FGF5, FGF6, FGF7, FGF7 (KGF), FGF8, FGF9, FGFR1, FGFR2, FGFR3, FGFR4, Fibrillin- 1, Fibrillin-2, Fibrinogen, Fibroblast growth factor 15 (FGF15), Fibronectin, Fibulin-2, Fibulin-5, Filaggrin-processed NMF (contextual), FLT1 (VEGFR1), FLT4 (VEGFR3), FN1, Follistatin, GAL1 / LGALS1, GAL3 / LGALS3, Gastrin, GCGR, GDNF, Ghrelin, GIP, GLP-1, GLP-2, Glucagon, GLUT4, HBEGF, Hepatic lipase, HGF, Histamine, HLA-DPB, HLA-DPB1, HMGB1, HSPG2, Hyaluronan, HYALURONAN, Hydrogen sulfide, ICAM1, ICOSLG, IFNA, IFNAR1, IFNAR2, IFNB, IFNG, IFNGR1, IFNGR2, IGF1, IGF1R, IGF2, IGHG4, IGLC1, IGLC7, IGLL5, IHH, IL-10, IL-11, IL-12, IL-17A, IL-17F, IL-18, IL-1A, IL-1B, IL-22, IL-23, IL-25, IL-33, IL-6, IL-8, IL10, IL10RA, IL10RB, IL12RB1, IL12RB2, IL15, IL17A, IL17RA, IL17RC, IL18R1, IL18RAP, IL1B, IL1R1, IL1R2, IL22, IL22RA1, IL33R (ST2 / IL1RL1), IL6, IL6R, IL7, INSR, Insulin, Insulin-like growth factor 1 (IGF1), Integrin alpha3 (ITGA3), Integrin alpha6 (ITGA6), Integrin betal (ITGB1), Integrin beta4 (ITGB4), Irisin, ITGA1, ITGA4, ITGA5, ITGA9, ITGAM / CDllb, ITGAV, ITGAX / CDllc, ITGB1, ITGB2 / CD18, ITGB3, ITGB5, ITGB7, Jaggedl, Jagged2, Kallidin, Kallikrein KLK14, Kallikrein KLK5, Kallikrein KLK7, KDR (VEGFR2), KITLG (SCF), KLB, L1CAM, Lactoferrin, LAMA4, LAMA5, LAMB1, LAMC1, Laminin, Laminin-332, Laminin-511, Laminin-521, LBP, LDLR, LECT2, LEKTI (SPINK5), LEPR, Leptin, Leukotriene B4, Leukotriene C4, Leukotriene D4, Leukotriene E4, LIF, Lipocalin-2, Lipoprotein lipase, Lipoxin A4, Lipoxin B4, LPS-binding protein, LRP8, LTBP1, LTBP2, LTBP4, Lumican, LY86 / MD-1, LY96 (MD-2), LY96 / MD-2, Lysophosphatidic acid, Lysozyme, LYVE1, MADCAM1, Mannose-binding lectin, Maresin 1, MASP2, Melatonin, MMP1, MMP10, MMP11, MMP12, MMP13, MMP14, MMP16, MMP2, MMP3, MMP4, MMP5, MMP6, 301645057.1MMP7, MMP8, MMP9, Motilin, MSR1 / SR-A1, MUC1, MUC16, MUC2, MUC4, MUC5AC, Myostatin (GDF8), N-cadherin (CDH2), NCAM1, NELL2, Netrin-1, Netrin-3, Netrin-4, Neurexin-1, Neurexin-2, Neurexin-3, Neurocan, Neuroligin-1, Neuroligin-2, Neuroligin-3, Neuropeptide Y, NGF, NIDI, NID2, Nidogen, Nidogen-1, Nidogen-2, Nitric oxide, Norepinephrine, NOTCH 1, NOTCH2NLB, NrCAM, NRTN, NT-3, NT-4, Occludin (OCLN), Omentin, OPG, Osteocalcin, Osteopontin, Oxyntomodulin, P2RX7, PAI-1, Pancreatic polypeptide, Parathyroid hormone, PDCD1LG2 (PD-L2), PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFRA, PDGFRB, PDPN (Podoplanin), PECAM1, Pentraxins PTX3, Periostin, Perlecan, Peroxynitrite, Plasminogen, Platelet- activating factor (PAF), PLG, POSTN, Properdin, Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), Prostaglandin F2a (PGF2a), Protectin DI, PSPN, PTX3, PYY, RANKL, RBP4, Reactive oxygen species, Reelin, RELN, Resistin, Resolvin DI, Resolvin D2, Resolvin El, RP105 / TLR5L, RSPO1, RSPO2, RSPO3, RSPO4, S100A1, S100A5, S100A6, S100A7, S100A7 (Psoriasin), S100A8, S100A9, SCARB1, Sclerostin, Secretin, Secretory IgA, SELE, SELE (E-selectin), Selenoprotein P, SELP, SELP (P-selectin), Semaphorin3A, Semaphorin3F, Semaphorin4D, Serotonin, SERPINE1, Serum amyloid A, SHH, SIGLEC1, SIGLEC10, SIGLEC14, SIGLEC7, SIGLEC9, SIRT1, Slitl, Slit2, Slit3, SLPI, Somatostatin, SPARC, Sphingosine- 1 -phosphate, SPON1, SPP1, SSTR2, Substance P, Tenascin-C, Tenascin-R, Tenascin-X, TGF-beta, TGF-betal (TGFB1), TGF-beta2 (TGFB2), TGF-beta3 (TGFB3), TGFA, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, THBS3, Thrombin, Thromboxane A2, Thyroxine (T4), TIE2, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TNC, TNF, TNFRSF1A, TNFRSF1B, TPO, Transferrin, TREM1, TREM2, Triiodothyronine (T3), TSLP, TSLP receptor (TSLPR / CRLF2), UDP, UTP, Vasoactive intestinal peptide, VCAM1, VCAN, VEGFA, VEGFC, VEGFD, VEGFR2 (KDR), VEGFR3 (FLT4), Versican, Visfatin, Vitronectin, VLDLR, VTCN1 (B7-H4), VTCN1 / B7-H4, WNT1, WNT10A, WNT10B, WNT11, WNT16, WNT2, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, and / or WNT9B. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for hearing loss additionally comprises one or more appended domains. In embodiments the appended protein is BNDF or BNDF mimetics.13. Cosmetic Applications

[0232] In embodiments, the cellular reprogramming protein modulates the immune processes of cosmetic applications. In embodiments, the cosmetic applications is selected from 301645057.1the group consisting of: improvement of skin appearance, tone, and texture; reduction in the appearance of fine lines and wrinkles; reduction of visible redness or blotchiness; mitigation of visible signs of photoaging; improvement of skin barrier function and hydration; reduction in the appearance of pores; improvement of skin firmness and elasticity; reduction of hyperpigmentation, dyschromia, or uneven tone; reduction in the appearance of acne-related blemishes; reduction in the appearance of rosacea-associated erythema; improvement of scar appearance; improvement of the appearance of cellulite or striae; enhancement of hair density, thickness, or luster; reduction in the appearance of dandruff or scalp flaking; enhancement of nail strength and appearance; and cosmetic improvement of periocular and perioral skin, hair loss, or hair discoloration and grayness.

[0233] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to for cosmetic applications. In embodiments, the FC domain of the cellular reprogramming protein for cosmetic applications comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprise ADAMIO, ADAM17, ADAMTS1, ADAMTS4, Adenosine, ADGRE3, ADORA2A, ADP, AGER, AGER (RAGE), AGER / RAGE, Agouti signaling protein (ASIP), Agrin, Alpha-MSH (POMC-derived), AMP, ANGPT1, ANGPT2, AREG, ATP, Beta-defensin 1 (hBDl), Beta-defensin 2 (hBD2), Beta-defensin 3 (hBD3), BGN, Biglycan, BMP2, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, Bradykinin, BTC, C-reactive protein, Cl, Clq, Clr, Cis, C2, C3, C3a, C3aRl, C4, C5, C5a, C5aRl / CD88, C5aR2, C6, C7, C8, C9, Calcitonin gene-related peptide (CGRP), cAMP, Carbon monoxide, Cathelicidin LL-37, CCBE1, CCL1, CCL10, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL2, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CD14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform, CD276 / B7-H3, CD36, CD44, CD80, CD86, Ceramide, cGMP, Claudin-1 (CLDN1), CLEC4E (MINCLE), CLEC4E / MINCLE, CLEC6A (Dectin-2), CLEC6A / Dectin-2, CLEC7A (Dectin- 1), CLEC7A / Dectin-1, COL18A1, COL1A1, COL3A1, COL4A1, COL4A2, COL5A1, COL6A1, Collagen 1, Collagen 10, Collagen 11, Collagen 12, Collagen 13, Collagen 14, Collagen 15, Collagen 16, Collagen 17,301645057.1Collagen 18, Collagen 19, Collagen 2, Collagen 20, Collagen 21, Collagen 22, Collagen 23, Collagen 24, Collagen 25, Collagen 26, Collagen 27, Collagen 28, Collagen 3, Collagen 4, Collagen 5, Collagen 6, Collagen 7, Collagen 8, Collagen 9, Collagen I, Collagen II, Collagen III, Collagen IV, Collagen V, Collagen VI, Collagen VII, Collagen XII, Collagen XIV, Collagen XVII (BP180), Corneodesmosin (CDSN), Corticotropin-releasing hormone (CRH), CR1 / CD35, CR2 / CD21, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, DCN, Decorin, Defensin alpha, Defensin beta, Delta-like 1, Delta-like 4, Desmocollin 1 (DSC1), Desmocollin 3 (DSC3), Desmoglein 1 (DSG1), Desmoglein 3 (DSG3), DHH, DLL4, Dopamine, E-cadherin (CDH1), EFEMP2, EGF, EGFR, Elafin (PI3), Elastin, EMILIN1, EMILIN2, Endocannabinoid 2-AG, Endocannabinoid anandamide, Endothelin-1 (EDN1), Epinephrine, ERBB2, ERBB3, ERBB4, EREG, F10, Fll, F12, F2, F2R / PAR1, F2RL1 / PAR2, F3, F5, F7, F8, F9, Factor B, Factor D, FBN3, FCAR / CD89, FCGR1A / CD64, FCGR2A / CD32, FCGR3A / CD16a, FCGR3B / CD16b, FGA, FGB, FGF1, FGF10, FGF11, FGF12, FGF13, FGF14, FGF15, FGF16, FGF17, FGF18, FGF19, FGF2, FGF20, FGF21, FGF22, FGF23, FGF3, FGF4, FGF5, FGF6, FGF7, FGF7 (KGF), FGF8, FGF9, FGFR1, FGFR2, FGFR3, FGG, Fibrillin-1, Fibrillin-2, Fibrinogen, Fibronectin, Fibulin-2, Fibulin-5, Filaggrin-processed NMF (contextual), FLT1 (VEGFR1), FLT4 (VEGFR3), FN1, GAL1 / LGALS1, GAL3 / LGALS3, HBEGF, Histamine, HLA-DPB, HLA-DPB1, HMGB1, HSPG2, HYALURONAN, Hydrogen sulfide, ICAM1, ICOSLG, IFNA, IFNAR1, IFNAR2, IFNB, IFNG, IFNGR1, IFNGR2, IGF1, IGF2, IGHG4, IGLC1, IGLC7, IGLL5, IHH, IL-1, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-17A, IL-17F, IL-18, IL-19, IL-1A, IL-1B, IL-2, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-3, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL10, IL10RA, IL10RB, IL12RB1, IL12RB2, IL15, IL17A, IL17RA, IL17RC, IL18R1, IL18RAP, IL1B, IL1R1, IL1R2, IL22, IL22RA1, IL33R (ST2 / IL1RL1), IL6, IL6R, IL7, Integrin alpha3 (ITGA3), Integrin alpha6 (ITGA6), Integrin betal (ITGB1), Integrin beta4 (ITGB4), ITGA1, ITGA4, ITGA5, ITGA9, ITGAM / CDllb, ITGAV, ITGAX / CDllc, ITGB1, ITGB2 / CD18, ITGB3, ITGB5, ITGB7, Jaggedl, Jagged2, Kallidin, Kallikrein KLK14, Kallikrein KLK5, Kallikrein KLK7, KDR (VEGFR2), KITLG (SCF), Lactoferrin, LAMA4, LAMA5, LAMB1, LAMC1, Laminin, Laminin-332, Laminin-511, Laminin-521, LBP, LEKTI (SPINK5), Leukotriene B4, Leukotriene C4, Leukotriene D4, Leukotriene E4, LIF, Lipoxin A4, Lipoxin B4, LPS-binding protein, LTA, LTB, LTBP1, LTBP2, LTBP4, Lumican, LY86 / MD-1, LY96 (MD-2), 301645057.1LY96 / MD-2, Lysophosphatidic acid, Lysozyme, LYVE1, MADCAM1, Mannose-binding lectin, Maresin 1, MASP2, Melatonin, MMP1, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP18, MMP19, MMP2, MMP20, MMP21, MMP22, MMP23, MMP24, MMP25, MMP26, MMP27, MMP28, MMP3, MMP4, MMP5, MMP6, MMP7, MMP8, MMP9, MSR1 / SR-A1, MUC1, MUC16, MUC2, MUC4, MUC5AC, N-cadherin (CDH2), Neuropeptide Y, NIDI, NID2, Nidogen, Nidogen-1, Nidogen-2, Nitric oxide, Norepinephrine, Occludin (OCLN), Osteopontin, P2RX7, PAI-1, PDCD1LG2, PDCD1LG2 (PD-L2), PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFC, PDGFD, PDGFRA, PDGFRB, PDPN (Podoplanin), PECAM1, Pentraxins PTX3, Periostin, Perlecan, Peroxynitrite, Plasminogen, Platelet-activating factor (PAF), PLG, POSTN, Properdin, Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), Prostaglandin F2a (PGF2a), Protectin DI, PTX3, Reactive oxygen species, RELN, Resolvin DI, Resolvin D2, Resolvin El, RP105 / TLR5L, RSPO1, RSPO2, RSPO3, RSPO4, S100A1, S100A6, S100A7, S100A7 (Psoriasin), S100A8, S100A9, Secretory IgA, SELE, SELE (E-selectin), SELP, SELP (P-selectin), Serotonin, SERPINE1, Serum amyloid A, SHH, SIGLEC1, SIGLEC10, SIGLEC14, SIGLEC7, SIGLEC9, SLPI, Somatostatin, SPARC, Sphingosine- 1 -phosphate, SPON1, SPP1, Substance P, Tenascin-C, Tenascin-X, TGF-betal (TGFB1), TGF-beta2 (TGFB2), TGF-beta3 (TGFB3), TGFA, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, THBS3, Thrombin, Thrombospondin- 1, Thrombospondin-2, Thromboxane A2, TIE2, TIMP1, TIMP2, TIMP3, TIMP4, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TNC, TNF, TNFRSF1A, TNFRSF1B, TNFSF10, TNFSF11, TNFSF12, TNFSF13, TNFSF14, TNFSF15, TNFSF4, TNFSF8, TNFSF9, TREM1, TREM2, TSLP, TSLP receptor (TSLPR / CRLF2), UDP, UTP, Vasoactive intestinal peptide, VCAM1, VCAN, VEGFA, VEGFB, VEGFC, VEGFD, VEGFR2 (KDR), VEGFR3 (FLT4), Versican, Vitronectin, VTCN1 (B7-H4), VTCN1 / B7-H4, VWF, WNT1, WNT10A, WNT10B, WNT11, WNT16, WNT2, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, and / or WNT9B. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for cosmetic applications additionally comprises one or more appended domains. In embodiments the appended protein is GHK-Cu.14. Sexual Dysfunction

[0234] In embodiments, the cellular reprogramming protein modulates the immune processes of sexual dysfunction. In embodiments, the sexual dysfunction is selected from the group consisting of: erectile dysfunction; decreased libido; anorgasmia; delayed ejaculation; 301645057.1premature ejaculation; arousal disorders; dyspareunia; genitopelvic pain and penetration disorder; vulvodynia or vestibulodynia; pelvic floor hypertonicity with inflammatory features; Peyronie’s disease; post-prostatectomy or post-pelvic surgery sexual dysfunction; endocrine-or metabolic-associated sexual dysfunction; neurogenic sexual dysfunction; medication-associated sexual dysfunction; and post-inflammatory sexual dysfunction.

[0235] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent sexual dysfunction. In embodiments, the FC domain of the cellular reprogramming protein for sexual dysfunction comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprise ACTH (POMC), ACTIVIN A, ACTIVIN B, ADAM 10, ADAM17, ADAMTS1, ADAMTS4, ADIPONECTIN, ADIPOQ, AGER, Aggrecan, AGTR1, AGTR2, ALBUMIN, ALDOSTERONE, AMH, AMHR2, AMYLA°N (IAPP), ANGIOTENSIN II, ANGIOTENSINOGEN, ANGPT1, ANGPT2, ANP (NPPA), ANTI-MULLERIAN HORMONE (AMH), AR, AREG, ARTN, AVPR1A, AVPR2, BDNF, BGN, BMP2, BMP4, BMP6, BMP7, BNP (NPPB), Brevican, C3, C3AR1, C5, C5AR1, CALCITONIN, CBG (SERPINA6), CCL11, CCL19, CCL2, CCL21, CCL5, CCR2, CCR5, CCR7, CD 14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform, CD80, CD86, CHROMOGRANIN A, CLU, CNTF, COL18A1, COL1A1, COL1A2, COL3A1, COL4A1, COL4A2, COL5A1, COL6A1, COL6A2, COL7A1, Collagen I, Collagen III, Collagen IV, Contactin-1, Contactin-2, CORTISOL, CRB1, CRELD1, CRP, CSF1, CTSB, CTSD, CX3CL1, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL2, CXCL8, CXCL9, CXCR4, CXCR5, DCN, DHEA, DHH, EDN1, EDNRA, EDNRB, EFEMP1, EGF, EGFL8, EGFR, ELN, Endothelin-1, Ephrin-Al, Ephrin-A2, Ephrin-A3, Ephrin-Bl, Ephrin-B2, EPO, ERBB2, ESRI, ESR2, ESTRADIOL, FAT3, FGA, FGB, FGF10, FGF19, FGF2, FGF21, FGF23, FGF7, FGF8, FGFR1, FGFR2, FGFR4, FGG, Fibronectin, FLT1, FLT4, FN1, FSH, FSHR, GASTRIN, GCGR, GDNF, GH (GROWTH HORMONE), GHR, GHRH, GHRL, GIP, GLP1, GLP2, GLUCAGON, GNRHR, HBEGF, HCG, HEG1, HLA-G, HSPG2, Hyaluronan, ICAM1, ICOSLG, IFNG, IGF1, IGF1R, IGF2, IGF2R, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, IHH, IL-10, IL-1B, IL-6, IL10, IL10RA, IL17A, IL17RA, ILIA, IL1B, IL1R1, IL1R2, IL22, IL22RA1, IL6, IL6R, IL8, INHIBIN A, INHIBIN301645057.1B, INS, INSR, INSULIN-LIKE GROWTH FACTOR 1 (IGF1), INSUEIN-EIKE GROWTH FACTOR 2 (IGF2), ITGA1, ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGAE, ITGAV, ITGB1, ITGB2, ITGB3, ITGB4, ITGB5, ITGB7, ITGB8, IZUMO1, JUNO, KDR, KISS1R, KISSPEPTIN, KEB, L1CAM, LAMA1, LAMA3, LAMA4, LAMA5, LAMB1, LAMB2, LAMC1, Laminin, LAMININ, LEP, LEPR, LEPTIN, LGALS1, LGALS3, LH, LHR, LIF, LRP8, LY96, MELATONIN, MMP1, MMP12, MMP14, MMP2, MMP3, MMP7, MMP9, MOTILIN, MUC1, MUC16, NCAM1, NELL2, Netrin-1, Netrin-3, Netrin-4, Neurexin-1, Neurexin-2, Neurexin-3, Neurocan, Neuroligin-1, Neuroligin-2, Neuroligin-3, NGF, NIDI, NID2, Nidogen, Nitric oxide synthase (eNOS), NOTCH1, NOTCH2NLB, NOTCH3, NPR 1, NPR 2, NPR 3, NR3C1 (GLUCOCORTICOID RECEPTOR), NR3C2 (MINERALOCORTICOID RECEPTOR), NrCAM, NRTN, NT-3, NT-4, OXTR, OXytocin, OXYTOCIN, PDCD1LG2, PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFRA, PDGFRB, Perlecan, PGR, PLG, POSTN, PRLR, PROGESTERONE, PROLACTIN, PROS1, PSPN, PTH, PTH1R, PTHRP, PYY, Reelin, RELAXIN, RENIN, RETINOL-BINDING PROTEIN 4, RSPO1, RSPO2, S100A5, SCUBE1, SECRETIN, SELE, SELP, Semaphorin3A, Semaphorin3F, Semaphorin4D, SERPINE1, SHH, Slitl, Slit2, Slit3, SOMATOSTATIN, SPARC, SPP1, Tenascin-C, Tenascin-R, TESTOSTERONE, TGFA, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, THYROGLOBULIN, THYROID PEROXIDASE, THYROXINE (T4), TLL1, TLR1, TLR2, TLR4, TLR5, TLR6, TLR9, TNC, TNF, TNFRSF1A, TNFRSF1B, TRANSTHYRETIN, TRIIODOTHYRONINE (T3), TSHR, VASOPRESSIN (A VP), VCAM1, VCAN, VDR, VEGFA, VEGFB, VEGFC, VEGFD, Versican, VITAMIN D (CALCITRIOL), VITAMIN D BINDING PROTEIN (GC), VTCN1, VWF, WNT1, WNT3, WNT3A, WNT4, WNT5A, WNT7A, WNT7B, ZP3, and / or ZP4. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for sexual dysfunction additionally comprises one or more appended domains. In embodiments the appended protein is Melanotan II fragment.15. Immunosenescence

[0236] In embodiments, the cellular reprogramming protein modulates the immune processes of immunosenescence. In embodiments, the immunosenescence is selected from the group consisting of: age-associated immune decline; impaired innate immunity; impaired adaptive immunity; chronic low-grade inflammation (‘inflammaging’); diminished vaccine responsiveness; impaired immune surveillance; dysregulated lymphocyte homeostasis; stem-cell exhaustion; and altered myeloid or lymphoid cell function.301645057.1

[0237] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent immunosenescence. In embodiments, the FC domain of the cellular reprogramming protein for immunosenescence comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprise ADAMIO, ADAM17, ADAMTS1, ADAMTS4, Adenosine, ADGRE3, Adiponectin, ADORA2A, ADP, Adrenomedullin, AGER, AGER (RAGE), AGER / RAGE, Agouti signaling protein (ASIP), Agrin, Albumin, Aldosterone, Alpha-MSH (POMC -derived), AMP, Amylin, Amylin (IAPP), Angiopoietin-like 3 (ANGPTL3), ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANGPTL6, ANGPTL8, Apelin, Apolipoprotein A-I, Apolipoprotein B, Apolipoprotein C-III, Apolipoprotein E, AREG, ATP, BDNF, Beta-defensin 1 (hBDl), Beta-defensin 2 (hBD2), Beta-defensin 3 (hBD3), BGN, Biglycan, Bile acids, BMP2, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, Bradykinin, BTC, C-reactive protein, Cl, Clq, Clr, Cis, C2, C3, C3a, C3aRl, C4, C5, C5a, C5aRl / CD88, C5aR2, C6, C7, C8, C9, Calcitonin gene-related peptide (CGRP), cAMP, Carbon monoxide, Cathelicidin LL-37, CCBE1, CCL17, CCL19, CCL2, CCL20, CCL21, CCL27, CCL28, CCL3, CCL4, CCL5, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CD14, CD274 CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform, CD36, CD44, CD80, CD86, Ceramide, cGMP, Chemerin, Cholecystokinin, Claudin-1 (CLDN1), CLEC4E (MINCLE), CLEC4E / MINCLE, CLEC6A (Dectin-2), CLEC6A / Dectin-2, CLEC7A (Dectin-1), CLEC7A / Dectin-1, COL18A1, COL1A1, COL3A1, COL4A1, COL4A2, COL5A1, COL6A1, Collagen I, Collagen II, Collagen III, Collagen IV, Collagen V, Collagen VI, Collagen VII, Collagen XII, Collagen XIV, Collagen XVII (BP180), Comeodesmosin (CDSN), Corticotropin-releasing hormone (CRH), Cortisol, CR1 / CD35, CR2 / CD21, CRP, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL2, CXCL3, CXCL8, CXCL9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, DCN, Decorin, Defensin alpha, Defensin beta, Delta- like 1, Delta- like 4, Desmocollin 1 (DSC1), Desmocollin 3 (DSC3), Desmoglein 1 (DSG1), Desmoglein 3 (DSG3), DHH, DKK 1, DLL4, Dopamine, E-cadherin (CDH1), EFEMP2, EGF, EGFR, Elafin (PI3), Elastin, EMILIN1, EMILIN2, Endocannabinoid 2- AG, Endocannabinoid anandamide, Endothelin-1, Endothelin-1 (EDN1), Epinephrine, ERBB2, ERBB3, ERBB4, EREG, F2R / PAR1, F2RL1 / PAR2, Factor B, Factor D, FBN3, FCAR / CD89, FCGR1A / CD64, FCGR2A / CD32, FCGR3A / CD16a, 301645057.1FCGR3B / CD16b, Fetuin-A, Fetuin-B, FGF1, FGF10, FGF18, FGF19, FGF2, FGF20, FGF21, FGF23, FGF4, FGF5, FGF6, FGF7, FGF7 (KGF), FGF8, FGF9, FGFR1, FGFR2, FGFR3, FGFR4, Fibrillin-1, Fibrillin-2, Fibrinogen, Fibroblast growth factor 15 (FGF15), Fibronectin, Fibulin-2, Fibulin-5, Filaggrin-processed NMF (contextual), FLT1 (VEGFR1), FLT4 (VEGFR3), FN1, Follistatin, GAL1 / LGALS1, GAL3 / LGALS3, Gastrin, GCGR, Ghrelin, GIP, GLP-1, GLP-2, Glucagon, GLUT4, HBEGF, Hepatic lipase, HGF, Histamine, HLA-DPB, HLA-DPB1, HMGB1, HSPG2, HYALURONAN, Hydrogen sulfide, ICAM1, ICOSLG, IFNA, IFNAR1, IFNAR2, IFNB, IFNG, IFNGR1, IFNGR2, IGF1, IGF1R, IGF2, IGHG4, IGLC1, IGLC7, IGLL5, IHH, IL-10, IL-11, IL-12, IL-17A, IL-17F, IL-18, IL-1A, IL-1B, IL-22, IL-23, IL-25, IL-33, IL-6, IL-8, IL10, IL10RA, IL10RB, IL12RB1, IL12RB2, IL15, IL17A, IL17RA, IL17RC, IL18R1, IL18RAP, IL1B, IL1R1, IL1R2, IL22, IL22RA1, IL33R (ST2 / IL1RL1), IL6, IL6R, IL7, INSR, Insulin, Insulin-like growth factor 1 (IGF1), Integrin alpha3 (ITGA3), Integrin alpha6 (ITGA6), Integrin betal (ITGB1), Integrin beta4 (ITGB4), Irisin, ITGA1, ITGA4, ITGA5, ITGA9, ITGAM / CDllb, ITGAV, ITGAX / CDllc, ITGB1, ITGB2 / CD18, ITGB3, ITGB5, ITGB7, Jaggedl, Jagged2, Kallidin, Kallikrein KLK14, Kallikrein KLK5, Kallikrein KLK7, KDR (VEGFR2), KITLG (SCF), KLB, Lactoferrin, LAMA4, LAMA5, LAMB1, LAMC1, Laminin, Laminin-332, Laminin-511, Laminin-521, LBP, LDLR, LECT2, LEKTI (SPINK5), LEPR, Leptin, Leukotriene B4, Leukotriene C4, Leukotriene D4, Leukotriene E4, LIF, Lipocalin-2, Lipoprotein lipase, Lipoxin A4, Lipoxin B4, LPS-binding protein, LTBP1, LTBP2, LTBP4, Lumican, LY86 / MD-1, LY96 (MD-2), LY96 / MD-2, Lysophosphatidic acid, Lysozyme, LYVE1, MADCAM1, Mannose-binding lectin, Maresin 1, MASP2, Melatonin, MMP1, MMP10, MMP11, MMP12, MMP13, MMP14, MMP16, MMP2, MMP3, MMP4, MMP5, MMP6, MMP7, MMP8, MMP9, Motilin, MSR1 / SR-A1, MUC1, MUC16, MUC2, MUC4, MUC5AC, Myostatin (GDF8), N-cadherin (CDH2), Neuropeptide Y, NIDI, NID2, Nidogen, Nidogen-1, Nidogen-2, Nitric oxide, Norepinephrine, Occludin (OCLN), Omentin, OPG, Osteocalcin, Osteopontin, Oxyntomodulin, P2RX7, PALI, Pancreatic polypeptide, Parathyroid hormone, PDCD1LG2 (PD-L2), PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFRA, PDGFRB, PDPN (Podoplanin), PECAM1, Pentraxins PTX3, Periostin, Perlecan, Peroxynitrite, Plasminogen, Plateletactivating factor (PAF), PLG, POSTN, Properdin, Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), Prostaglandin F2a (PGF2a), Protectin DI, PTX3, PYY, RANKL, RBP4, Reactive oxygen species, RELN, Resistin, Resolvin DI, Resolvin D2, Resolvin El, RP105 / TLR5L, RSPO1, RSPO2, RSPO3, RSPO4, S100A1, S100A6, S100A7, S100A7 (Psoriasin), S100A8, S100A9, SCARB1, Sclerostin, Secretin, Secretory IgA, SELE, SELE (E-selectin), 301645057.1Selenoprotein P, SELP, SELP (P-selectin), Serotonin, SERPINE1, Serum amyloid A, SHH, SIGEEC1, SIGEEC10, SIGEEC14, SIGLEC7, SIGLEC9, SIRT1, SLPI, Somatostatin, SPARC, Sphingosine- 1 -phosphate, SPON1, SPP1, SSTR2, Substance P, Tenascin-C, Tenascin-X, TGF-beta, TGF-betal (TGFB1), TGF-beta2 (TGFB2), TGF-beta3 (TGFB3), TGFA, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, THBS3, Thrombin, Thromboxane A2, Thyroxine (T4), TIE2, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TNC, TNF, TNFRSF1A, TNFRSF1B, TPO, Transferrin, TREM1, TREM2, Triiodothyronine (T3), TSLP, TSLP receptor (TSEPR / CREF2), UDP, UTP, Vasoactive intestinal peptide, VCAM1, VCAN, VEGFA, VEGFC, VEGFD, VEGFR2 (KDR), VEGFR3 (FLT4), Versican, Visfatin, Vitronectin, VLDLR, VTCN1 (B7-H4), VTCN1 / B7-H4, WNT1, WNT10A, WNT10B, WNT11, WNT16, WNT2, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, and / or WNT9B. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for immunosenescence additionally comprises one or more appended domains. In embodiments the appended protein is Thymosin alpha 1 or fragments thereof.16. Chronic and Recurrent Infectious Diseases

[0238] In embodiments, the cellular reprogramming protein modulates the immune processes of chronic and recurrent infectious diseases. In embodiments, the chronic and recurrent infectious diseases is selected from the group consisting of: chronic bacterial, viral, fungal, parasitic, or polymicrobial infections; recurrent mucosal or cutaneous infections; persistent intracellular infections; biofilm-associated infections; latent or smoldering infections; and infection-associated inflammatory or immune-dysregulated states that fail to fully resolve.

[0239] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent chronic and / or recurrent infectious diseases. In embodiments, the FC domain of the cellular reprogramming protein for chronic and recurrent infectious diseases comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprise ACAN, ADAM10, ADAM17, ADAMTS1, ADAMTS4, ADAMTS5, Adenosine, ADGRE3,301645057.1Adiponectin, ADORA2A, ADP, Adrenomedullin, AGER, AGER (RAGE), AGER / RAGE, Agouti signaling protein (ASIP), AGRIN, AGTR1, AGTR2, Albumin, Aldosterone, ALDOSTERONE, Alpha-MSH (POMC -derived), AMP, Amylin, Amylin (IAPP), Angiopoietin-like 3 (ANGPTL3), ANGIOTENSIN II, ANGIOTENSINOGEN, ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANGPTL6, ANGPTL8, ANP (NPPA), Apelin, Apolipoprotein A-I, Apolipoprotein B, Apolipoprotein C-III, Apolipoprotein E, AREG, ATP, AVPR1A, AVPR2, BDNF, Beta-defensin 1 (hBDl), Beta-defensin 2 (hBD2), Beta-defensin 3 (hBD3), BGLAP, BGN, Biglycan, Bile acids, BMP2, BMP4, BMP6, BMP7, BNP (NPPB), BPIFA1, Bradykinin, BTC, C-reactive protein, Cl, Clq, Clr, Cis, C2, C3, C3a, C3aRl, C3AR1, C4, C5, C5a, C5AR1, C5aRl / CD88, C5aR2, C6, C7, C8, C9, CALCITONIN, Calcitonin gene-related peptide (CGRP), cAMP, Carbon monoxide, Cathelicidin LL-37, CCBE1, CCL11, CCL17, CCL19, CCL2, CCL20, CCL21, CCL25, CCL27, CCL28, CCL3, CCL4, CCL5, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CD 14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform, CD36, CD44, CD80, CD86, Ceramide, cGMP, Chemerin, Cholecystokinin, Claudin-1 (CLDN1), CLEC4E, CLEC4E (MINCLE), CLEC4E / MINCLE, CLEC6A, CLEC6A (Dectin-2), CLEC6A / Dectin-2, CLEC7A, CLEC7A (Dectin-1), CLEC7A / Dectin-1, COL11A1, COL12A1, COL14A1, COL15A1, COL18A1, COL1A1, COL1A2, COL3A1, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL5A1, COL6A1, COL7A1, Collagen I, Collagen III, Collagen IV, Collagen V, Collagen VI, Collagen VII, Collagen XII, Collagen XIV, Collagen XVII (BP180), Collagen XVIII, COMP, Comeodesmosin (CDSN), Corticotropinreleasing hormone (CRH), Cortisol, CR1 / CD35, CR2 / CD21, CRP, CSF1, CSF1R, CTSK, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL2, CXCL8, CXCL9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, DCN, Decorin, Defensin alpha, Defensin beta, Desmocollin 1 (DSC1), Desmocollin 3 (DSC3), Desmoglein 1 (DSG1), Desmoglein 3 (DSG3), DKK 1, Dopamine, E-cadherin (CDH1), EDN1, EFEMP2, EGF, EGFR, Elafin (PI3), Elastin, ELN, EMILIN1, EMILIN2, Endocannabinoid 2-AG, Endocannabinoid anandamide, Endothelin-1, Endothelin-1 (EDN1), Epinephrine, ERBB2, ERBB3, ERBB4, EREG, ERYTHROPOIETIN (EPO), F2R / PAR1, F2RL1 / PAR2, Factor B, Factor D, FBN1, FBN3, FCAR / CD89, FCGR1A / CD64, FCGR2A / CD32, FCGR3A / CD16a, FCGR3B / CD16b, Fetuin-A, Fetuin-B, FGF10, FGF19, FGF2, FGF21, FGF23, FGF6, FGF7, FGF7 (KGF), FGFR1, FGFR2, FGFR3, FGFR4, Fibrillin-1, Fibrillin-2, Fibrinogen, Fibroblast growth factor 15 (FGF15), Fibronectin, Fibulin-2, Fibulin-5, Filaggrin-processed NMF (contextual), FLT1, FLT1 (VEGFR1), FLT4 (VEGFR3), FN1, Follistatin, Gastrin, GCGR, 301645057.1GDF5, GH, Ghrelin, GIP, GLP-1, GLP-2, Glucagon, GLUT4, HBEGF, Hepatic lipase, HGF, Histamine, HLA-DPB, HLA-DPB1, HMGB1, HSPG2, HYALURONAN, Hydrogen sulfide, IBSP, ICAM1, ICOSLG, IFNA, IFNAR1, IFNAR2, IFNB, IFNG, IFNGR1, IFNGR2, IGF1, IGF1R, IGF2, IGHG4, IGLC1, IGLC7, IGLL5, IHH, IL-10, IL-12, IL-17A, IL-17F, IL-18, ILIA, IL-1B, IL-22, IL-23, IL-25, IL-33, IL-6, IL-8, IL10, IL10RA, IL10RB, IL12RB1, IL12RB2, IL13, IL13RA1, IL15, IL17A, IL17RA, IL17RC, IL18R1, IL18RAP, ILIA, IL1B, IL1R1, IL1R2, IL1RL1 (ST2), IL22, IL22RA1, IL25, IL33, IL33R (ST2 / IL1RL1), IL6, IL6R, IL7, IL8, INS, INSR, Insulin, Insulin-like growth factor 1 (IGF1), Integrin alpha3 (ITGA3), Integrin alpha6 (ITGA6), Integrin betal (ITGB1), Integrin beta4 (ITGB4), Irisin, ITGA1, ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGA9, ITGAE, ITGAM / CDllb, ITGAV, ITGAX / CDllc, ITGB1, ITGB2 / CD18, ITGB3, ITGB4, ITGB5, ITGB6, ITGB7, ITGB8, Kallidin, Kallikrein KLK14, Kallikrein KLK5, Kallikrein KLK7, KDR, KDR (VEGFR2), KITLG (SCF), KLB, KLOTHO, Lactoferrin, LAMA2, LAMA3, LAMA4, LAMA5, LAMB1, LAMB2, LAMC1, Laminin- 111, Laminin-332, Laminin-511, Laminin-521, LBP, LDLR, LECT2, LEKTI (SPINK5), LEPR, Leptin, Leukotriene B4, Leukotriene C4, Leukotriene D4, Leukotriene E4, Lipocalin-2, Lipoprotein lipase, Lipoxin A4, Lipoxin B4, LPS-binding protein, LTBP1, LTBP2, LTBP4, LUBRICIN, Lumican, LY86 / MD-1, LY96, LY96 (MD-2), LY96 / MD-2, Lysophosphatidic acid, Lysozyme, LYVE1, MADCAM1, Mannose-binding lectin, Maresin 1, MASP2, MATN1, MATN3, Melatonin, MMP1, MMP12, MMP13, MMP14, MMP2, MMP3, MMP7, MMP8, MMP9, Motilin, MSR1 / SR-A1, MUC1, MUC16, MUC2, MUC4, MUC5AC, MUC5B, Myostatin (GDF8), N-cadherin (CDH2), NELLI, Neuropeptide Y, NIDI, NID2, Nidogen-1, Nidogen-2, Nitric oxide, NODI, NOD2, Norepinephrine, Occludin (OCLN), Omentin, OPG, Osteocalcin, Osteopontin, Oxyntomodulin, P2RX7, PAI-1, Pancreatic polypeptide, Parathyroid hormone, PDCD1LG2, PDCD1LG2 (PD-L2), PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFRA, PDGFRB, PDPN (Podoplanin), PECAM1, Pentraxins PTX3, Periostin, Perlecan, Peroxynitrite, Plasminogen, Platelet-activating factor (PAF), PLG, POSTN, PRG4, Properdin, Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), Prostaglandin F2a (PGF2a), Protectin DI, PTH, PTH1R, PTX3, PYY, RANKL, RBP4, Reactive oxygen species, REG3A, REG3G, RELN, RENIN, Resistin, Resolvin DI, Resolvin D2, Resolvin El, RP105 / TLR5L, RSPO1, RSPO2, RSPO3, S100A1, S100A6, S100A7, S100A7 (Psoriasin), S100A8, S100A9, SCARB1, SCGB1A1, Sclerostin, Secretin, Secretory IgA, SELE, SELE (E-selectin), Selenoprotein P, SELP, SELP (P-selectin), Serotonin, SERPINE1, Serum amyloid A, SFTPA1, SFTPA2, SFTPB, SFTPC, SFTPD, SHH, SIGLEC1, SIGLEC10, SIGLEC14, SIGLEC7, SIGLEC9, SIRT1, SLPI, Somatostatin, SOST, SPARC, 301645057.1Sphingosine- 1 -phosphate, SPON1, SPP1, SSTR2, Substance P, Tenascin-C, Tenascin-X, TGF-beta, TGF-betal, TGF-betal (TGFB1), TGF-beta2, TGF-beta2 (TGFB2), TGF-beta3, TGF-beta3 (TGFB3), TGFA, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, THBS3, Thrombin, Thromboxane A2, Thyroxine (T4), TIE2, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TNC, TNF, TNFRSF11A (RANK), TNFRSF11B (OPG), TNFRSF1A, TNFRSF1B, TNFSF11 (RANKL), TPO, Transferrin, TREM1, TREM2, Triiodothyronine (T3), TSLP, TSLP receptor (TSLPR / CRLF2), UDP, UMOD, UTP, Vasoactive intestinal peptide, VASOPRESSIN (A VP), VCAM1, VCAN, VEGFA, VEGFB, VEGFC, VEGFD, VEGFR2 (KDR), VEGFR3 (FLT4), Versican, Visfatin, VITAMIN D (CALCITRIOL), Vitronectin, VLDLR, VTCN1, VTCN1 (B7-H4), VTCN1 / B7-H4, VWCE, WNT10A, WNT10B, WNT3, WNT3A, WNT4, WNT5A, WNT7B, and / or WNT9B. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for chronic and recurrent infectious diseases additionally comprises one or more appended domains. In embodiments the appended protein is a MSH KPV and / or Tat peptide.17. Regenerative and Transplant Medicine

[0240] In embodiments, the cellular reprogramming protein modulates the immune processes of regenerative and transplant medicine. In embodiments, the regenerative and transplant medicine is selected from the group consisting of: tissue regeneration; organ regeneration; stem-cell-based repair; biomaterial or scaffold integration; graft tolerance enhancement; prevention of graft rejection; modulation of ischemia-reperfusion injury; facilitation of organ engraftment; reduction of fibrosis after injury or transplantation; enhancement of wound and tissue repair; and restoration of functional tissue architecture.

[0241] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to for regenerative and / or transplant medicine. In embodiments, the FC domain of the cellular reprogramming protein for regenerative and transplant medicine comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprise AC AN, ACTIVIN A, ACTIVIN B, ADAM10, ADAM17, ADAMTS1, ADAMTS4, Adiponectin, ADIPOQ,301645057.1Adrenomedullin, AGER, Agrin, AGTR1, AGTR2, Albumin, Aldosterone, AMHR2, Amylin, Amylin (IAPP), Angiopoietin-like 3 (ANGPTL3), ANGIOTENSIN II, ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANGPTL6, ANGPTL8, ANP (NPPA), ANTI-MULLERIAN HORMONE (AMH), Apelin, Apolipoprotein A-I, Apolipoprotein B, Apolipoprotein C-III, Apolipoprotein E, AR, AREG, BDNF, BGLAP, BGN, Biglycan, Bile acids, BMP2, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BNP (NPPB), BTC, Cl, C2, C3, C3AR1, C4, C5, C5AR1, C6, C7, C8, C9, CALCITONIN, CCL1, CCL10, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL2, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCR2, CCR5, CCR7, CD14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 41g-isoform, CD36, CD80, CD86, Chemerin, Cholecystokinin, COL11A1, COL12A1, COL14A1, COL15A1, COL18A1, COL1A1, COL1A2, COL3A1, COL4A1, COL4A2, COL5A1, COL6A1, COL6A2, COL7A1, Collagen 1, Collagen 10, Collagen 11, Collagen 12, Collagen 13, Collagen 14, Collagen 15, Collagen 16, Collagen 17, Collagen 18, Collagen 19, Collagen 2, Collagen 20, Collagen 21, Collagen 22, Collagen 23, Collagen 24, Collagen 25, Collagen 26, Collagen 27, Collagen 28, Collagen 3, Collagen 4, Collagen 5, Collagen 6, Collagen 7, Collagen 8, Collagen 9, Collagen I, Collagen II, Collagen III, Collagen IV, Collagen V, Collagen VI, COMP, Cortisol, CRELD1, CRP, CSF1, CSF1R, CTSB, CTSD, CTSK, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCR4, CXCR5, DCN, Decorin, Delta-like 1, Delta-like 4, DHH, DKK 1, DLL4, EDN1, EDNRA, EDNRB, EGF, EGFR, ELN, Endothelin-1, ERBB2, EREG, ESRI, ESR2, ESTRADIOL, F10, Fll, F12, F2, F3, F5, F7, F8, F9, Fetuin-A, Fetuin-B, FGA, FGB, FGF1, FGF10, FGF11, FGF12, FGF13, FGF14, FGF15, FGF16, FGF17, FGF18, FGF19, FGF2, FGF20, FGF21, FGF22, FGF23, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, FGFR1, FGFR2, FGFR4, FGG, Fibroblast growth factor 15 (FGF15), Fibronectin, FLT1, FLT4, FN1, Follistatin, FSH, FSHR, GAL1 / LGALS1, GAL3 / LGALS3, Gastrin, GCGR, GDF5, GH, Ghrelin, GHRL, GIP, GLP-1, GLP-2, Glucagon, GLUT4, GNRHR, HBEGF, HCG, HEG1, Hepatic lipase, HGF, HLA-G, HMGB1, HSPG2, IBSP, ICAM1, ICOSLG, IFNB, IFNG, IGF1, IGF1R, IGF2, IGF2R, IHH, IL-1, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-1A, IL-1B, IL-2, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-3, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL10, IL17A, IL17RA, ILIA, IL1B, IL1R1, IL1R2, IL22, IL22RA1, IL6, IL6R, IL8, INHIBIN A, INHIBIN B, INS, INSR, Insulin, Insulin-like growth factor 1 (IGF1), Irisin, ITGA1, ITGA2, ITGA3, 301645057.1ITGA4, ITGA5, ITGA6, ITGAE, ITGAV, ITGB1, ITGB2, ITGB3, ITGB4, ITGB5, ITGB7, ITGB8, IZUMO1, Jaggedl, Jagged2, JUNO, KDR, KISS1R, KISSPEPTIN, KLB, KLOTHO, LAMA1, LAMA2, LAMA3, LAMA4, LAMA5, LAMB 1, LAMB2, LAMC1, Laminin, LDLR, LECT2, LEP, LEPR, Leptin, LGALS1, LGALS3, LH, LHR, LIF, Lipocalin-2, Lipoprotein lipase, LTA, LTB, LUBRICIN, Lumican, LY96, MATN1, MATN3, MMP1, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP18, MMP19, MMP2, MMP20, MMP21, MMP22, MMP23, MMP24, MMP25, MMP26, MMP27, MMP28, MMP3, MMP4, MMP5, MMP6, MMP7, MMP8, MMP9, Motilin, MUC1, MUC16, Myostatin (GDF8), NELLI, NIDI, NID2, Nidogen, Nitric oxide, Nitric oxide synthase (eNOS), NOTCH3, NPR 1, NPR 2, NPR 3, Omentin, OPG, Osteocalcin, Osteopontin, OXTR, Oxyntomodulin, OXytocin, Pancreatic polypeptide, Parathyroid hormone, PDCD1LG2, PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFC, PDGFD, PDGFRA, PDGFRB, Periostin, Perlecan, PGR, PLG, POSTN, PRG4, PRLR, PROGESTERONE, PROLACTIN, PROS1, PTH, PTH1R, PYY, RANKL, RBP4, RELAXIN, Resistin, RSPO1, RSPO2, RSPO3, RSPO4, S100A8, S100A9, SCARB1, Sclerostin, SCUBE1, Secretin, SELE, Selenoprotein P, SELP, SERPINE1, SHH, SIRT1, Somatostatin, SOST, SPARC, SPP1, SSTR2, Tenascin-C, TESTOSTERONE, TGF-beta, TGFA, TGFB 1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, Thrombospondin- 1, Thrombospondin-2, Thyroxine (T4), TIMP1, TIMP2, TIMP3, TIMP4, TLL1, TLR1, TLR2, TLR4, TLR5, TLR6, TLR9, TNC, TNF, TNFRSF11A (RANK), TNFRSF11B (OPG), TNFRSF1A, TNFRSF1B, TNFSF10, TNFSF11, TNFSF11 (RANKL), TNFSF12, TNFSF13, TNFSF14, TNFSF15, TNFSF4, TNFSF8, TNFSF9, TPO, Transferrin, Triiodothyronine (T3), VCAM1, VC AN, VEGFA, VEGFB, VEGFC, VEGFD, Versican, Visfatin, VITAMIN D (CALCITRIOL), Vitronectin, VLDLR, VTCN1, VWF, WNT1, WNT10A, WNT10B, WNT11, WNT16, WNT2, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, ZP3, and / or ZP4. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for regenerative and transplant medicine additionally comprises one or more appended domains. In embodiments the appended protein is defensin peptide.18. Psychosis Disorders

[0242] In embodiments, the cellular reprogramming protein modulates the immune processes of psychosis disorders. In embodiments, the psychosis disorders is selected from the group consisting of: acute psychosis; chronic psychotic disorders; schizophrenia spectrum disorders; schizoaffective disorder; bipolar disorder with psychotic features; depression with 301645057.1psychotic features; substance-associated psychosis; autoimmune or inflammatory psychosis; infection-associated psychosis; stress-related psychosis; and neurodevelopmental or neurodegenerative psychotic disorders.

[0243] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent psychosis disorders. In embodiments, the FC domain of the cellular reprogramming protein for psychosis disorders comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprise ACTH (POMC), ADAMIO, ADAM17, ADAMTS1, ADAMTS4, Adenosine, ADGRE3, Adiponectin, ADIPONECTIN, ADIPOQ, ADORA2A, ADP, Adrenomedullin, AGER / RAGE, Aggrecan, Agrin, Albumin, ALBUMIN, Aldosterone, ALDOSTERONE, AMH, AMP, Amylin, Amylin (IAPP), AMYLA°N (IAPP), Angiopoietin-like 3 (ANGPTL3), ANGIOTENSIN II, ANGIOTENSINOGEN, ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANGPTL6, ANGPTL8, ANP (NPPA), Apelin, Apolipoprotein A-I, Apolipoprotein B, Apolipoprotein C-III, Apolipoprotein E, AR, ARTN, ATP, AVPR1A, AVPR2, BDNF, Biglycan, Bile acids, BMP2, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BNP (NPPB), Bradykinin, Brevican, C-reactive protein, Cl, Clq, Clr, Cis, C2, C3, C3a, C3aRl, C4, C5, C5a, C5aRl / CD88, C5aR2, C6, C7, C8, C9, CALCITONIN, Calcitonin gene-related peptide (CGRP), cAMP, Carbon monoxide, Cathelicidin LL-37, CBG (SERPINA6), CCL2, CCL20, CCL3, CCL4, CCL5, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CD14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform, CD36, CD80, CD86, Ceramide, cGMP, Chemerin, Cholecystokinin, CHROMOGRANIN A, CLEC4E / MINCLE, CLEC6A / Dectin-2, CLEC7A / Dectin-1, CLU, CNTF, COL1A1, COL3A1, COL4A1, Collagen I, Collagen II, Collagen III, Collagen IV, Collagen V, Collagen VI, Contactin- 1, Contactin-2, Corticotropin-releasing hormone (CRH), Cortisol, CORTISOL, CR1 / CD35, CR2 / CD21, CRB1, CRP, CX3CL1, CXCL1, CXCL10, CXCL11, CXCL12, CXCL14, CXCL2, CXCL3, CXCL8, CXCL9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, Decorin, Defensin alpha, Defensin beta, Delta-like 1, Delta-like 4, DHEA, DHH, DKK 1, DLL4, Dopamine, EFEMP1, EGFL8, Endocannabinoid 2-AG, Endocannabinoid anandamide, Endothelin-1, Ephrin-Al, Ephrin-A2, Ephrin-A3, Ephrin-Bl, Ephrin-B2, Epinephrine, EPO, ESRI, ESR2, F2R / PAR1, F2RL1 / PAR2, Factor B, Factor D,301645057.1FAT3, FCAR / CD89, FCGR1A / CD64, FCGR2A / CD32, FCGR3A / CD16a, FCGR3B / CD16b, Fetuin-A, Fetuin-B, FGF1, FGF10, FGF18, FGF19, FGF2, FGF20, FGF21, FGF23, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, FGFR1, FGFR4, Fibrinogen, Fibroblast growth factor 15 (FGF15), Fibronectin, FN1, Follistatin, FSH, FSHR, GAL1 / LGALS1, GAL3 / LGALS3, Gastrin, GASTRIN, GCGR, GDNF, GH (GROWTH HORMONE), GHR, Ghrelin, GHRH, GHRL, GIP, GLP-1, GLP-2, GLP1, GLP2, Glucagon, GLUCAGON, GLUT4, HCG, Hepatic lipase, HGF, Histamine, HLA-DPB, HLA-DPB1, HMGB1, HSPG2, Hyaluronan, Hydrogen sulfide, ICAM1, ICOSLG, IFNA, IFNAR1, IFNAR2, IFNB, IFNG, IFNGR1, IFNGR2, IGF1, IGF1R, IGF2, IGF2R, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, IGHG4, IGLC1, IGLC7, IGLL5, IHH, IL-10, IL-11, IL-12, IL-17A, IL-18, IL-1A, IL-1B, IL-22, IL-6, IL-8, IL10, IL10RA, IL10RB, IL12RB1, IL12RB2, IL17A, IL17RA, IL17RC, IL18R1, IL18RAP, ILIA, IL1B, IL1R1, IL1R2, IL22, IL22RA1, IL6, IL6R, INS, INSR, Insulin, Insulin-like growth factor 1 (IGE1), INSULIN-LIKE GROWTH EACTOR 1 (IGE1), INSULIN-LIKE GROWTH EACTOR 2 (IGE2), Irisin, ITGA1, ITGA5, ITGAM / CDllb, ITGAV, ITGAX / CDllc, ITGB1, ITGB2 / CD18, ITGB3, Jaggedl, Jagged2, Kallidin, KLB, L1CAM, Lactoferrin, Laminin, LAMININ, LBP, LDLR, LECT2, LEP, LEPR, Leptin, LEPTIN, Leukotriene B4, Leukotriene C4, Leukotriene D4, Leukotriene E4, LH, LHR, LIE, Lipocalin-2, Lipoprotein lipase, Lipoxin A4, Lipoxin B4, LPS-binding protein, LRP8, LTBP1, Lumican, LY86 / MD-1, LY96 / MD-2, Lysophosphatidic acid, Lysozyme, Mannose-binding lectin, Maresin 1, MASP2, Melatonin, MELATONIN, MMP1, MMP10, MMP11, MMP12, MMP13, MMP14, MMP16, MMP2, MMP3, MMP4, MMP5, MMP6, MMP7, MMP8, MMP9, Motilin, MOTILIN, MSR1 / SR-A1, MUC1, MUC2, MUC5AC, Myostatin (GDE8), NCAM1, NELL2, Netrin-1, Netrin-3, Netrin-4, Neurexin-1, Neurexin-2, Neurexin-3, Neurocan, Neuroligin-1, Neuroligin-2, Neuroligin-3, Neuropeptide Y, NGE, Nidogen, Nitric oxide, Norepinephrine, NOTCH1, NOTCH2NLB, NR3C1 (GLUCOCORTICOID RECEPTOR), NR3C2 (MINERALOCORTICOID RECEPTOR), NrCAM, NRTN, NT-3, NT-4, Omentin, OPG, Osteocalcin, OXTR, Oxyntomodulin, OXYTOCIN, P2RX7, PALI, Pancreatic polypeptide, Parathyroid hormone, PDCD1LG2 / PD-L2, PDGLA, PDGEB, PECAM1, Pentraxins PTX3, Perlecan, Peroxynitrite, Plasminogen, Platelet- activating factor (PAP), POSTN, PRLR, PROLACTIN, Properdin, Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), Prostaglandin P2a (PGP2a), Protectin DI, PSPN, PTH, PTH1R, PTHRP, PTX3, PYY, RANKL, RBP4, Reactive oxygen species, Reelin, RENIN, Resistin, Resolvin DI, Resolvin D2, Resolvin El, RETINOL-BINDING PROTEIN 4, RP105 / TLR5L, RSPO1, RSPO2, RSPO3, RSPO4, S100A1, S100A5, S100A6, S100A7, S100A8, S100A9, SCARB1, 301645057.1Sclerostin, Secretin, SECRETIN, Secretory IgA, SELE, Selenoprotein P, SELP, Semaphorin3A, Semaphorin3F, Semaphorin4D, Serotonin, Serum amyloid A, SHH, SIGLEC1, SIGLEC10, SIGLEC14, SIGLEC7, SIGLEC9, SIRT1, Slitl, Slit2, Slit3, Somatostatin, SOMATOSTATIN, SPARC, Sphingosine- 1 -phosphate, SSTR2, Substance P, Tenascin-C, Tenascin-R, TESTOSTERONE, TGF-beta, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS3, Thrombin, Thromboxane A2, THYROGLOBULIN, THYROID PEROXIDASE, Thyroxine (T4), THYROXINE (T4), TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TNF, TNFRSF1A, TNFRSF1B, TPO, Transferrin, TRANSTHYRETIN, TREM1, TREM2, Triiodothyronine (T3), TRIIODOTHYRONINE (T3), TSHR, UDP, UTP, Vasoactive intestinal peptide, VASOPRESSIN (A VP), VCAM1, VDR, VEGFA, VEGFB, VEGFC, Versican, Visfatin, VITAMIN D (CALCITRIOL), VITAMIN D BINDING PROTEIN (GC), Vitronectin, VLDLR, VTCN1 / B7-H4, WNT1, WNT10A, WNT10B, WNT11, WNT16, WNT2, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, and / or WNT9B. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for psychosis disorders additionally comprises one or more appended domains. In embodiments, the appended protein is NPY13-36.19. Chronic Pain

[0244] In embodiments, the cellular reprogramming protein modulates the immune processes of chronic pain. In embodiments, the chronic pain is selected from the group consisting of: inflammatory pain; neuropathic pain; nociplastic pain; centralized pain; musculoskeletal pain; visceral pain; cancer-associated pain; post-infectious pain; post-surgical pain; trauma-associated chronic pain; and chronic pain associated with immune dysregulation or neuroimmune activation.

[0245] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or cure chronic pain. In embodiments, the FC domain of the cellular reprogramming protein for chronic pain comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprise ADAM10, ADAM12, ADAM17, ADAMTS1, ADAMTS4,301645057.1Adiponectin, Adrenomedullin, AGER, Aggrecan, Agrin, Albumin, Aldosterone, Amylin, Amylin (IAPP), Angiopoietin-like 3 (ANGPTL3), ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANGPTL6, ANGPTL8, Apelin, Apolipoprotein A-I, Apolipoprotein B, Apolipoprotein C-III, Apolipoprotein E, AREG, ARTN, BDNF, BGN, Biglycan, Bile acids, BMP2, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, Brevican, BTC, Cl, C2, C3, C4, C5, C6, C7, C8, C9, CCBE1, CCL1, CCL10, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL2, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCR7, CD14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform„ CD36, CD44, CD80, CD86, Chemerin, Cholecystokinin, CLU, CNTF, COL18A1, COL1A1, COL3A1, COL4A1, COL4A2, COL5A1, COL6A1, Collagen 1, Collagen 10, Collagen 11, Collagen 12, Collagen 13, Collagen 14, Collagen 15, Collagen 16, Collagen 17, Collagen 18, Collagen 19, Collagen 2, Collagen 20, Collagen 21, Collagen 22, Collagen 23, Collagen 24, Collagen 25, Collagen 26, Collagen 27, Collagen 28, Collagen 3, Collagen 4, Collagen 5, Collagen 6, Collagen 7, Collagen 8, Collagen 9, Collagen I, Collagen II, Collagen III, Collagen IV, Collagen V, Collagen VI, Contactin-1, Contactin-2, Cortisol, CRB1, CRP, CX3CL1, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCR3, CXCR4, CXCR5, DCN, Decorin, Delta- like 1, Delta- like 4, DHH, DKK 1, DLL4, Dystroglycan, EFEMP1, EGF, EGFL8, EMILIN1, EMILIN2, Endothelin-1, Ephrin-Al, Ephrin-A2, Ephrin-A3, Ephrin-Bl, Ephrin-B2, EREG, F10, Fll, F12, F2, F3, F5, F7, F8, F9, FAT3, Fetuin-A, Fetuin-B, FGA, FGB, FGF1, FGF10, FGF11, FGF12, FGF13, FGF14, FGF15, FGF16, FGF17, FGF18, FGF19, FGF2, FGF20, FGF21, FGF22, FGF23, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, FGFR1, FGFR2, FGFR4, FGG, Fibroblast growth factor 15 (FGF15), Fibronectin, FET1 (VEGFR1), FET4 (VEGFR3), FN1, Follistatin, GAE1 / EGAES1, GAE3 / EGAES3, Galectin-1 / EGAES1, Galectin-3 / EGAES3, Gastrin, GCGR, GDNF, Ghrelin, GIP, GEP-1, GEP-2, Glucagon, GEUT4, HBEGF, Hepatic lipase, HGF, HSPG2, Hyaluronan, HYAEURONAN, ICAM1, ICOSEG, IFNB, IFNG, IGF1, IGF1R, IGF2, IHH, IE-1, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-1A, IL-1B, IL-2, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-3, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL10, IL15, IL17A, IL1B, IL22, IL6, IL6R, IL7, INSR, Insulin, Insulin-like growth factor 1 (IGF1), Integrin a7, Integrin P1D, Irisin, ITGA1, ITGA4, ITGA5, ITGA9, ITGAV, ITGB1, ITGB3, ITGB5, ITGB7, Jaggedl, Jagged2, KDR (VEGFR2), KLB, L1CAM, LAMA4, LAMA5, LAMB1, LAMC1, 301645057.1Laminin, LDLR, LECT2, LEPR, Leptin, LIF, Lipocalin-2, Lipoprotein lipase, LRP8, LTA, LTB, Lumican, LYVE1, MADCAM1, MMP1, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP18, MMP19, MMP2, MMP20, MMP21, MMP22, MMP23, MMP24, MMP25, MMP26, MMP27, MMP28, MMP3, MMP4, MMP5, MMP6, MMP7, MMP8, MMP9, Motilin, Myostatin (GDF8), MYOSTATIN / GDF8, NCAM1, NELL2, Netrin-1, Netrin-3, Netrin-4, Neurexin-1, Neurexin-2, Neurexin-3, Neurocan, Neuroligin-1, Neuroligin-2, Neuroligin-3, NGF, NIDI, NID2, Nidogen, Nitric oxide, NOTCH1, NOTCH2NLB, NrCAM, NRTN, NT-3, NT-4, Omentin, OPG, Osteocalcin, Osteopontin, Oxyntomodulin, Pancreatic polypeptide, Parathyroid hormone, PDCD1LG2, PDCD1LG2 (PD-L2), PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFC, PDGFD, PDGFRA, PDGFRB, PDPN (Podoplanin), PECAM1, Periostin, Perlecan, PLG, POSTN, PSPN, PYY, RANKL, RBP4, Reelin, RELN, Resistin, RSPO1, RSPO2, RSPO3, RSPO4, S100A5, S100A8, S100A9, SCARB1, Sclerostin, Secretin, SELE, Selenoprotein P, SELP, Semaphorin3A, Semaphorin3F, Semaphorin4D, SERPINE1, SHH, SIRT1, Slitl, Slit2, Slit3, Somatostatin, SPARC, SPON1, SPP1, SSTR2, Tenascin-C, Tenascin-R, TGF-beta, TGFA, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, Thrombospondin- 1, Thrombospondin-2, Thyroxine (T4), TIE2, TIMP1, TIMP2, TIMP3, TIMP4, TLR2, TLR4, TLR9, TNC, TNF, TNFRSF1A, TNFSF10, TNFSF11, TNFSF12, TNFSF13, TNFSF14, TNFSF15, TNFSF4, TNFSF8, TNFSF9, TPO, Transferrin, Triiodothyronine (T3), uPA / PLAU, VCAM1, VCAN, VEGFA, VEGFB, VEGFC, VEGFD, Versican, Visfatin, Vitronectin, VLDLR, VTCN1 (B7-H4), VWF, WNT1, WNT10A, WNT10B, WNT11, WNT16, WNT2, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, a-Sarcoglycan, 0-Sarcoglycan, y-Sarcoglycan, and / or 6-Sarcoglycan. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for chronic pain additionally comprises one or more appended domains. In embodiments the appended protein is Endomorphin 1 and / or Enkephalin.20. Autoimmune Disease

[0246] In embodiments, the cellular reprogramming protein modulates the immune processes of autoimmune disease. In embodiments, the autoimmune disease is selected from the group consisting of: systemic autoimmune disease; organ-specific autoimmune disease; autoantibody-mediated disease; T-cell-mediated disease; complement-mediated disease; vasculitis; connective tissue disease; overlap syndromes; and post-infectious or immune-triggered autoimmunity.301645057.1

[0247] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to treat or prevent autoimmune disease. In embodiments, the FC domain of the cellular reprogramming protein for autoimmune disease comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprise ACTIVIN A, ACTIVIN B, ADAMIO, ADAM17, ADAMTS1, ADAMTS4, ADAMTS5, Adenosine, ADGRE3, ADIPOQ, ADORA2A, ADP, AGER, AGER (RAGE), AGER / RAGE, Agouti signaling protein (ASIP), AGTR1, AGTR2, Alpha-MSH (POMC -derived), AMHR2, AMP, ANGIOTENSIN II, ANGPT1, ANGPT2, ANP (NPPA), ANTI-MULLERIAN HORMONE (AMH), AR, AREG, ATP, Beta-defensin 1 (hBDl), Beta-defensin 2 (hBD2), Beta-defensin 3 (hBD3), BGN, Biglycan, BMP2, BMP4, BMP7, BNP (NPPB), Bradykinin, BTC, C-reactive protein, Cl, Clq, Clr, Cis, C2, C3, C3a, C3aRl, C3AR1, C4, C5, C5a, C5AR1, C5aRl / CD88, C5aR2, C6, C7, C8, C9, Calcitonin gene-related peptide (CGRP), cAMP, Carbon monoxide, Cathelicidin LL-37, CCBE1, CCL11, CCL17, CCL19, CCL2, CCL20, CCL21, CCL25, CCL27, CCL28, CCL3, CCL4, CCL5, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CD14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform, CD36, CD44, CD80, CD86, Ceramide, cGMP, Cholecystokinin, Claudin-1 (CLDN1), CLEC4E (MINCLE), CLEC4E / MINCLE, CLEC6A (Dectin-2), CLEC6A / Dectin-2, CLEC7A (Dectin-1), CLEC7A / Dectin-1, COL18A1, COL1A1, COL1A2, COL3A1, COL4A1, COL4A2, COL5A1, COL6A1, COL6A2, COL7A1, Collagen I, Collagen III, Collagen IV, Collagen V, Collagen VI, Collagen VII, Collagen XII, Collagen XIV, Collagen XVII (BP180), Collagen XVIII, Corneodesmosin (CDSN), Corticotropin-releasing hormone (CRH), CR1 / CD35, CR2 / CD21, CRELD1, CRP, CSF1, CTSB, CTSD, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL2, CXCL8, CXCL9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, DCN, Decorin, Defensin alpha, Defensin beta, Desmocollin 1 (DSC1), Desmocollin 3 (DSC3), Desmoglein 1 (DSG1), Desmoglein 3 (DSG3), Dopamine, E-cadherin (CDH1), EDN1, EDNRA, EDNRB, EFEMP2, EGF, EGFR, Elafin (PI3), Elastin, ELN, EMILIN 1, EMILIN2, Endocannabinoid 2- AG, Endocannabinoid anandamide, Endothelin-1, Endothelin-1 (EDN1), Epinephrine, ERBB2, ERBB3, ERBB4, EREG, ESRI, ESR2, ESTRADIOL, F2R / PAR1, F2RL1 / PAR2, Factor B, Factor D, FBN3, FCAR / CD89, FCGR1A / CD64, FCGR2A / CD32, FCGR3A / CD16a, FCGR3B / CD16b, FGA, FGB, FGF10, FGF19, FGF2, FGF21, FGF7, FGF7 301645057.1(KGF), FGF8, FGFR1, FGFR2, FGFR3, FGFR4, FGG, Fibrillin- 1, Fibrillin-2, Fibrinogen, Fibronectin, Fibulin-2, Fibulin-5, Filaggrin-processed NMF (contextual), FLT1, FLT1 (VEGFR1), FLT4, FLT4 (VEGFR3), FN1, FSH, FSHR, Gastrin, Ghrelin, GHRL, GIP, GLP-1, GLP-2, GNRHR, HBEGF, HCG, HEG1, Histamine, HLA-DPB, HLA-DPB1, HLA-G, HMGB1, HSPG2, HYALURONAN, Hydrogen sulfide, ICAM1, ICOSLG, IFNA, IFNAR1, IFNAR2, IFNB, IFNG, IFNGR1, IFNGR2, IGF1, IGF1R, IGF2, IGF2R, IGHG4, IGLC1, IGLC7, IGLL5, IHH, IL-10, IL-12, IL-17A, IL-17F, IL-18, IL-1A, IL-1B, IL-22, IL-23, IL-25, IL-33, IL-6, IL-8, IL10, IL10RA, IL10RB, IL12RB1, IL12RB2, IL15, IL17A, IL17RA, IL17RC, IL18R1, IL18RAP, ILIA, IL1B, IL1R1, IL1R2, IL22, IL22RA1, IL33R (ST2 / IL1RL1), IL6, IL6R, IL7, IL8, INHIBIN A, INHIBIN B, INS, Integrin alpha3 (ITGA3), Integrin alpha6 (ITGA6), Integrin betal (ITGB1), Integrin beta4 (ITGB4), ITGA1, ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGA9, ITGAE, ITGAM / CDllb, ITGAV, ITGAX / CDllc, ITGB1, ITGB2, ITGB2 / CD18, ITGB3, ITGB4, ITGB5, ITGB7, ITGB8, IZUMO1, JUNO, Kallidin, Kallikrein KLK14, Kallikrein KLK5, Kallikrein KLK7, KDR, KDR (VEGFR2), KISS1R, KISSPEPTIN, KITLG (SCF), Lactoferrin, LAMA1, LAMA3, LAMA4, LAMA5, LAMB1, LAMB2, LAMC1, Laminin, Laminin-Ill, Laminin-332, Laminin-511, Laminin-521, LBP, LEKTI (SPINK5), LEP, Leukotriene B4, Leukotriene C4, Leukotriene D4, Leukotriene E4, LGALS1, LGALS3, LH, LHR, LIF, Lipoxin A4, Lipoxin B4, LPS-binding protein, LTBP1, LTBP2, LTBP4, Lumican, LY86 / MD-1, LY96, LY96 (MD-2), LY96 / MD-2, Lysophosphatidic acid, Lysozyme, LYVE1, MADCAM1, Mannose-binding lectin, Maresin 1, MASP2, Melatonin, MMP1, MMP12, MMP13, MMP14, MMP2, MMP3, MMP7, MMP8, MMP9, Motilin, MSR1 / SR-A1, MUC1, MUC16, MUC2, MUC4, MUC5AC, N-cadherin (CDH2), Neuropeptide Y, NIDI, NID2, Nidogen-1, Nidogen-2, Nitric oxide, Nitric oxide synthase (eNOS), NODI, NOD2, Norepinephrine, NOTCH3, NPR 1, NPR 2, NPR 3, Occludin (OCLN), Osteopontin, OXTR, OXytocin, P2RX7, PALI, PDCD1LG2, PDCD1LG2 (PD-L2), PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFRA, PDGFRB, PDPN (Podoplanin), PECAM1, Pentraxins PTX3, Periostin, Perlecan, Peroxynitrite, PGR, Plasminogen, Platelet-activating factor (PAF), PLG, POSTN, PRLR, PROGESTERONE, PROLACTIN, Properdin, PROS1, Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), Prostaglandin F2a (PGF2a), Protectin DI, PTX3, PYY, Reactive oxygen species, REG3A, REG3G, RELAXIN, RELN, Resolvin DI, Resolvin D2, Resolvin El, RP105 / TLR5L, RSPO1, RSPO2, RSPO3, S100A1, S100A6, S100A7, S100A7 (Psoriasin), S100A8, S100A9, SCUBE1, Secretin, Secretory IgA, SELE, SELE (E-selectin), SELP, SELP (P-selectin), Serotonin, SERPINE1, Serum amyloid A, SHH, SIGLEC1, SIGLEC10, SIGLEC14, SIGLEC7, SIGLEC9, SLPI, Somatostatin, SPARC, 301645057.1Sphingosine- 1 -phosphate, SPON1, SPP1, Substance P, Tenascin-C, Tenascin-X, TESTOSTERONE, TGF-betal, TGF-betal (TGFB1), TGF-beta2, TGF-beta2 (TGFB2), TGF-beta3, TGF-beta3 (TGFB3), TGFA, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, THBS3, Thrombin, Thromboxane A2, TIE2, TLL1, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TNC, TNF, TNFRSF1A, TNFRSF1B, TREM1, TREM2, TSLP, TSLP receptor (TSLPR / CRLF2), UDP, UTP, Vasoactive intestinal peptide, VCAM1, VCAN, VEGFA, VEGFB, VEGFC, VEGFD, VEGFR2 (KDR), VEGFR3 (FLT4), Versican, Vitronectin, VTCN1, VTCN1 (B7-H4), VTCN1 / B7-H4, VWCE, VWF, WNT10A, WNT10B, WNT3, WNT3A, WNT4, WNT5A, WNT9B, ZP3, and / or ZP4. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for autoimmune disease additionally comprises one or more appended domains. In embodiments the appended protein is a-MSH KPV.21. Microbial Response

[0248] In embodiments, the cellular reprogramming protein modulates the immune processes of microbial response. In embodiments, the microbial response is selected from the group consisting of: innate responses to pathogens; adaptive immune responses to pathogens; antiviral responses; antibacterial responses; antifungal responses; antiparasitic responses; mucosal defense; epithelial barrier defense; pathogen clearance; immune memory formation; and immune tolerance to commensals.

[0249] In embodiments, the cellular reprogramming protein comprises an Fc domain and at least two or more polypeptides. The cellular reprogramming protein can also comprises an appended domain on either end. In embodiments, the appended domain is on the C-terminus. In embodiments, the cellular reprogramming domain is used to enhance microbial response. In embodiments, the FC domain of the cellular reprogramming protein for microbial response comprises IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA. The FC domain can be wildtype, an activating mutant, or an inhibitory mutant. In embodiments, the two or more polypeptides comprise ADAM10, ADAM17, ADAMTS1, ADAMTS4, ADAMTS5, Adenosine, ADGRE3, ADORA2A, ADP, AGER, AGER (RAGE), AGER / RAGE, Agouti signaling protein (ASIP), Alpha-MSH (POMC -derived), AMP, ANGPT1, ANGPT2, AREG, ATP, Beta-defensin 1 (hBDl), Beta-defensin 2 (hBD2), Beta-defensin 3 (hBD3), BGN, Biglycan, BMP2, BMP4, BMP7, BPIFA1, Bradykinin, BTC, C-reactive protein, Cl, Clq, Clr, Cis, C2, C3, C3a, C3aRl, C3AR1, C4, C5, C5a, C5AR1, C5aRl / CD88, C5aR2, C6, C7, C8,301645057.1C9, Calcitonin gene-related peptide (CGRP), cAMP, Carbon monoxide, Cathelicidin LL-37, CCBE1, CCL11, CCL17, CCL19, CCL2, CCL20, CCL21, CCL25, CCL27, CCL28, CCL3, CCL4, CCL5, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CD 14, CD274, CD276, CD276 (B7-H3) 21g isoform, CD276 (B7-H3) 4Ig-isoform, CD36, CD44, CD80, CD86, Ceramide, cGMP, Cholecystokinin, Claudin-1 (CLDN1), CLEC4E, CLEC4E (MINCLE), CLEC4E / MINCLE, CLEC6A, CLEC6A (Dectin-2), CLEC6A / Dectin-2, CLEC7A, CLEC7A (Dectin-1), CLEC7A / Dectin-1, COL18A1, COL1A1, COL3A1, COL4A1, COL4A2, COL5A1, COL6A1, COL7A1, Collagen I, Collagen III, Collagen IV, Collagen V, Collagen VI, Collagen VII, Collagen XII, Collagen XIV, Collagen XVII (BP180), Collagen XVIII, Comeodesmosin (CDSN), Corticotropin-releasing hormone (CRH), CR1 / CD35, CR2 / CD21, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL2, CXCL8, CXCL9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, DCN, Decorin, Defensin alpha, Defensin beta, Desmocollin 1 (DSC1), Desmocollin 3 (DSC3), Desmoglein 1 (DSG1), Desmoglein 3 (DSG3), Dopamine, E-cadherin (CDH1), EFEMP2, EGF, EGFR, Elafin (PI3), Elastin, ELN, EMILIN1, EMILIN2, Endocannabinoid 2-AG, Endocannabinoid anandamide, Endothelin-1 (EDN1), Epinephrine, ERBB2, ERBB3, ERBB4, EREG, F2R / PAR1, F2RL1 / PAR2, Factor B, Factor D, FBN1, FBN3, FCAR / CD89, FCGR1A / CD64, FCGR2A / CD32, FCGR3A / CD16a, FCGR3B / CD16b, FGF10, FGF19, FGF2, FGF21, FGF7, FGF7 (KGF), FGFR1, FGFR2, FGFR3, FGFR4, Fibrillin-1, Fibrillin-2, Fibrinogen, Fibronectin, Fibulin-2, Fibulin-5, Filaggrin-processed NMF (contextual), FLT1 (VEGFR1), FLT4 (VEGFR3), FN1, Gastrin, Ghrelin, GIP, GLP-1, GLP-2, HBEGF, Histamine, HLA-DPB, HLA-DPB1, HMGB1, HSPG2, HYALURONAN, Hydrogen sulfide, ICAM1, ICOSLG, IFNA, IFNAR1, IFNAR2, IFNB, IFNG, IFNGR1, IFNGR2, IGHG4, IGLC1, IGLC7, IGLL5, IHH, IL-10, IL-12, IL-17A, IL-17F, IL-18, IL-1A, IL-1B, IL-22, IL-23, IL-25, IL-33, IL-6, IL-8, IL10, IL10RA, IL10RB, IL12RB1, IL12RB2, IL13, IL13RA1, IL15, IL17A, IL17RA, IL17RC, IL18R1, IL18RAP, ILIA, IL1B, IL1R1, IL1R2, IL1RL1 (ST2), IL22, IL22RA1, IL25, IL33, IL33R (ST2 / IL1RL1), IL6, IL6R, IL7, IL8, Integrin alpha3 (ITGA3), Integrin alpha6 (ITGA6), Integrin betal (ITGB1), Integrin beta4 (ITGB4), ITGA1, ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGA9, ITGAE, ITGAM / CDllb, ITGAV, ITGAX / CDllc, ITGB1, ITGB2 / CD18, ITGB3, ITGB4, ITGB5, ITGB6, ITGB7, ITGB8, Kallidin, Kallikrein KLK14, Kallikrein KLK5, Kallikrein KLK7, KDR (VEGFR2), KITLG (SCF), Lactoferrin, LAMA3, LAMA4, LAMA5, LAMB1, LAMC1, Laminin-Ill, Laminin-332, Laminin-511, Laminin-521, LBP, LEKTI (SPINK5), Leukotriene B4, Leukotriene C4, Leukotriene D4, Leukotriene E4, Lipoxin A4, Lipoxin B4, LPS-binding protein, LTBP1, LTBP2, LTBP4, Lumican, 301645057.1LY86 / MD-1, LY96, LY96 (MD-2), LY96 / MD-2, Lysophosphatidic acid, Lysozyme, LYVE1, MADCAM1, Mannose-binding lectin, Maresin 1, MASP2, Melatonin, MMP1, MMP12, MMP13, MMP14, MMP2, MMP3, MMP7, MMP8, MMP9, Motilin, MSR1 / SR-A1, MUC1, MUC16, MUC2, MUC4, MUC5AC, MUC5B, N-cadherin (CDH2), Neuropeptide Y, NIDI, NID2, Nidogen-1, Nidogen-2, Nitric oxide, NODI, NOD2, Norepinephrine, Occludin (OCLN), Osteopontin, P2RX7, PALI, PDCD1LG2, PDCD1LG2 (PD-L2), PDCD1LG2 / PD-L2, PDGFA, PDGFB, PDGFRA, PDGFRB, PDPN (Podoplanin), PECAM1, Pentraxins PTX3, Periostin, Perlecan, Peroxynitrite, Plasminogen, Platelet- activating factor (PAF), PLG, POSTN, Properdin, Prostaglandin D2 (PGD2), Prostaglandin E2 (PGE2), Prostaglandin F2a (PGF2a), Protectin DI, PTX3, PYY, Reactive oxygen species, REG3A, REG3G, RELN, Resolvin DI, Resolvin D2, Resolvin El, RP105 / TLR5L, RSPO1, RSPO2, RSPO3, S100A1, S100A6, S100A7, S100A7 (Psoriasin), S100A8, S100A9, SCGB1A1, Secretin, Secretory IgA, SELE, SELE (E-selectin), SELP, SELP (P-selectin), Serotonin, SERPINE1, Serum amyloid A, SFTPA1, SFTPA2, SFTPB, SFTPC, SFTPD, SHH, SIGLEC1, SIGLEC10, SIGLEC14, SIGLEC7, SIGLEC9, SLPI, Somatostatin, SPARC, Sphingosine- 1 -phosphate, SPON1, SPP1, Substance P, Tenascin-C, Tenascin-X, TGF-betal, TGF-betal (TGFB1), TGF-beta2, TGF-beta2 (TGFB2), TGF-beta3, TGF-beta3 (TGFB3), TGFA, TGFB 1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS1, THBS2, THBS3, Thrombin, Thromboxane A2, TIE2, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TNC, TNF, TNFRSF1A, TNFRSF1B, TREM1, TREM2, TSLP, TSLP receptor (TSLPR / CRLF2), UDP, UTP, Vasoactive intestinal peptide, VCAM1, VCAN, VEGFA, VEGFB, VEGFC, VEGFD, VEGFR2 (KDR), VEGFR3 (FLT4), Versican, Vitronectin, VTCN1, VTCN1 (B7-H4), VTCN1 / B7-H4, VWCE, WNT10A, WNT10B, WNT3, WNT3A, WNT5A, and / or WNT9B. The two or more polypeptides can be the same or different. In embodiments, the cellular reprogramming protein for microbial response additionally comprises one or more appended domains. In embodiments the appended protein is Histatin 5 or fragments thereof.II. Cellular Reprogramming Constructs and Uses Thereof

[0250] Embodiments of the disclosure include use of any of the engineered proteins encompassed herein. Embodiments of the disclosure include compositions that can return type I inflammation, type II inflammation, or both to homeostasis. The return to homeostasis can occur because the cellular reprogramming protein is anti-inflammatory, inflammatory, or both anti-inflammatory and inflammatory.301645057.1

[0251] Embodiment of the disclosure include an cellular reprogramming protein comprising a Fc domain and at least two extracellular polypeptides. The cellular reprogramming polypeptides in the cellular reprogramming protein may be the same or different. For example, FIG. 1 shows the different types of engineered cellular reprogramming proteins which comprise one Fc domain and two cellular reprogramming polypeptides. Further, there can be a linking polypeptide between each of the domains (cellular reprogramming polypeptides), such as a ((GGGS)x4) linker. Each of these proteins can be included in the library. This modular design of the library allows for disease specific fine-tuning at multiple scales.

[0252] Embodiments of the disclosure include compositions that reprogram the cellular processes of cancer, fibrosis, neurodegeneration, deconditioning, viral latency and reactivation, metabolic dysfunction, barrier dysfunction, digestive disorders, cardiovascular disease, wound healing, respiratory disease, urinary and excretory system disorders, infertility, osteoporosis and fracture, hearing loss, cosmetic applications, sexual dysfunction, immunosenescence, chronic and recurrent infectious diseases, regenerative and transplant medicine, psychosis disorders, chronic pain, autoimmune disease, and microbial response. Embodiment of the disclosure include a cellular reprogramming protein comprising a Fc domain and at least two extracellular polypeptides. The cellular reprogramming polypeptides in the cellular reprogramming protein may be the same or different. For example, FIG. 1 shows the different types of engineered cellular reprogramming proteins which comprise one Fc domain and two cellular reprogramming polypeptides. The cellular reprogramming polypeptides may be the same polypeptide or may be different polypeptides. Further, there can be a linking polypeptide between each of the domains (cellular reprogramming polypeptides), such as a ((GGGS)x4) linker. Each of these proteins can be included in the library. This modular design of the library allows for disease specific fine-tuning at multiple scales.

[0253] In embodiments, the cellular reprogramming polypeptides (“B” and “C” in the figure above) that are used in combination with a Fc domain include B7 proteins. In embodiments, the cellular reprogramming polypeptides for fibrosis for example, can include 2Ig-B7-H3, 4Ig-B7-H3, PD-E1 (B7-H1), PD-E2 (B7-DC), CD80 (B7-1), CD83, CD86 (B7-2), ICOS (B7-H2), B7-H4 (VTCN1), B7-H5 (VISTA), B7-H6 (NCR3EG1), B7-H7 (HHEA2), MHC-I, MHC-II, CD40, IE-18, IE-37, TNFa, IFNy, TGF-[3, Cytokines, IE-15, HEA-F, CD19,301645057.1CD4, HLA-B, and IL-17RB, The cellular reprogramming polypeptides can comprise mutations that alter their immune functions, either increasing or decreasing immune activity.

[0254] In embodiments, the cellular reprogramming protein comprises at least one Fc domain. In embodiments, the Fc domain is a human Fc domain. The Fc domain can be a wildtype domain or it can comprise an activating mutation or an inhibitory mutation. The Fc domain can be IgGl, IgG2, IgG3, IgG4, IgD, IgE, IgM, and / or IgA.

[0255] By coupling immune stimulation with immune suppression in a single chain biologic, a therapeutic solution is engineered that can be tuned at multiple scales, providing a disease- specific immune re-engagement that can be refined based on cellular localization, biologically relevant immune cell states or subsets, pharmacokinetics and pharmacodynamics, and to fit within existing treatment paradigms.

[0256] In embodiments, the activity and stability within each folded domain can be modulated with known point mutations from the literature and emerging or discoverable point mutations. For example, the immunomodulatory properties of the IgGl Fc domain can be influenced by the LALA mutation with inhibits FcgR mutations. Similarly, activating mutations are also known and have been incorporated into the cellular reprogramming protein library. Finally, the circulation time of the constructs can also be modulated via known mutations to the FcRn binding domain.

[0257] Note that any of the fusion proteins described herein can also be conjugated with bifunctional chelates enabling radioisotope labeling of said proteins. These radioligands can be used for PET, SPECT or MRI imaging, or for radiotheranostic applications using appropriate alpha, beta or Auger emitting isotopes.

[0258] In some embodiments, the fusion proteins are additionally fused to an appended protein. The appended proteins can be appended to either the C or the N terminus. The extension protein can be a known protein such as GLP1 or Titin, for example. The fusion protein can be linked thorough a linker, such as (GGGS)x4, or a protease cleavage linker (Fig.71). These linkers may be selected to improve targeting or therapeutic index through either local, systemic, or state dependent activation. As an example MMP2 / MMP9 sites might improve local delivery of appended domains and peptides at local sites of inflammation improving their cell targeting and potentially improving therapeutic index. In embodiments, the appended domain is a small molecule toxin, immunostimulant, p28 (azurin fragment), 301645057.1Flagellin and derivatives, Ac SDKP, Humanin, MOTS c, LL 37, C peptide fragment, Thymosin P4 fragment, GLP1, GIP, GLP 2 fragment, Apelin 13, KPV, VIP fragment, Uroguanylin fragment, Kisspeptin 10, PTH(1-14), BDNF mimetic GSB 106, GHK Cu, Melanotan II fragment, Thymosin al fragment, a MSH KPV, Defensin fragment, Thymosin p4(l-4), NPY1336, Endomorphin 1, and / or Histatin 5 fragment.

[0259] In some embodiments, the engineered proteins comprise di-sulfide bonded dimers, and as such, cells can be co-transfected with plasmids containing two different constructs, thus enabling the production of multimers of well-defined heterodimers.

[0260] In some embodiments, nucleotides encoding the cellular reprogramming can also be used therapeutically, where depending on the application the delivery of either DNA or mRNA (both natural and modified for stability and decreased immunogenicity) into cells to produce the single-chain biologies in situ rather than delivering the single-chain protein modulator itself. That is, embodiments of the disclosure include polynucleotides (DNA or RNA) that encode for a protein that is at least 80% similar to any one of SEQ ID NOs: 1-26, with or without a signaling peptide or his tag. In embodiments, the DNA or RNA can be delivered into mice or humans to generate cellular reprogramming proteins in vivo.A. Use in Individuals

[0261] Embodiments of the disclosure are the use of the cellular reprogramming proteins in individuals in need thereof. Example uses include, for example, suppressing irAEs associated with cancer immunotherapy including fibrosis, suppressing irAEs associated with cancer cell therapies (CAR-T, etc.), targeting immuno- senescence to improve cancer vaccine and general vaccine efficacy, treating inflammation-driven diseases (e.g., MASH, NASH, SLE, psoriasis, RA, etc.), treating GVHD in AML, treating or preventing radiation induced fibrosis, inflammatory cardiovascular, and inflammatory neurodegenerative diseases. Embodiments of the disclosure include the treatment of Castleman disease. In embodiments, the cellular reprogramming proteins can also be used to reprogram cells in the cases of cancer, fibrosis, neurodegeneration, deconditioning, viral latency and reactivation, metabolic dysfunction, barrier dysfunction, digestive disorders, cardiovascular disease, wound healing, respiratory disease, urinary and excretory system disorders, infertility, osteoporosis and fracture, hearing loss, cosmetic applications, sexual dysfunction, immunosenescence, chronic and recurrent infectious diseases, regenerative and transplant medicine, psychosis disorders, chronic pain,301645057.1autoimmune disease, and microbial response targeting extracellular protein domains (Figs. 131 and 132).III. Methods of Treatment

[0262] In some embodiments, the cellular reprogramming constructs of the disclosure are utilized for methods of treatment for an individual in need thereof. Embodiments of the disclosure include methods of treating an individual for cancer, fibrosis, neurodegeneration, deconditioning, viral latency and reactivation, metabolic dysfunction, barrier dysfunction, digestive disorders, cardiovascular disease, wound healing, respiratory disease, urinary and excretory system disorders, infertility, osteoporosis and fracture, hearing loss, cosmetic applications, sexual dysfunction, immunosenescence, chronic and recurrent infectious diseases, regenerative and transplant medicine, psychosis disorders, chronic pain, autoimmune disease, and microbial response, for example. The individual may utilize the treatment method of the disclosure as an initial treatment or after (and / or with) another treatment. If the other treatment is a biologic, the cellular reprogramming constructs can be attached to the biologic. In cancer embodiments, the immunotherapy methods may be tailored to the need of an individual based on the severity of symptoms and / or disease, and in at least some cases the cellular reprogramming protein therapy may be modified during the course of treatment for the individual.A. Pharmaceutical Compositions and Administration

[0263] Also provided herein are pharmaceutical compositions and formulations comprising cellular reprogramming proteins and a pharmaceutically acceptable carrier.

[0264] Pharmaceutical compositions and formulations as described herein can be prepared by mixing the active ingredients (the cellular reprogramming protein) having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 22ndedition, 2012), in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol;301645057.1cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn- protein complexes); and / or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersion agents such as soluble neutral- active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in US Patent Publication Nos. 2005 / 0260186 and 2006 / 0104968. In one aspect, a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases. The therapeutic cellular reprogramming protein composition may be administered hourly, daily or weekly, for example.

[0265] The dose may vary depending upon the age and the size of a subject to be administered, target disease, conditions, route of administration, and the like. Various delivery systems are known and can be used to administer the pharmaceutical composition of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu et al. (1987) J. Biol. Chem. 262:4429-4432). Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, topical, and oral routes. Administration can be systemic or local. The pharmaceutical composition can be also delivered in a vesicle, in particular a liposome (see Langer (1990) Science 249:1527-1533; Treat et al. (1989) in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez Berestein and Fidler (eds.), Liss, New York, pp. 353-365; Lopez-Berestein, ibid., pp. 317-327. In certain situations, the pharmaceutical composition can be delivered in a controlled release system.

[0266] Injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by methods publicly known. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the engineered301645057.1protein described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared is preferably filled in an appropriate ampoule.

[0267] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0268] In some aspects, the protein constructs are conjugated or fused to an imaging agent, a cytotoxic agent, a metal, or a radioactive moiety. In some aspects, the imaging agent is a fluorophore. In some aspects, the radioactive moiety is Zr-89, Cu-64, F-18, Y-90, Lu- 177, Ac-225, At-211, or Pb-212.B. Combination Therapies

[0269] In certain embodiments, the compositions and methods of the present embodiments involve an cellular reprogramming protein in combination with at least one additional therapy. For cancer embodiments, the additional therapy may be radiation therapy, chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, or a combination of the foregoing. The additional therapy may be in the form of adjuvant or neoadjuvant therapy. For pathogenic conditions, the additional therapy may comprise one or more antibiotics, antivirals, and so forth.

[0270] An cellular reprogramming protein of the disclosure may be administered before, during, after, or in various combinations relative to other therapy, such as cancer therapy. The administrations may be in intervals ranging from concurrently to minutes to days to weeks. In embodiments where the therapy is provided to a patient separately from an additional therapeutic agent, one would generally ensure that a significant period of time301645057.1did not expire between the time of each delivery. It is contemplated that one may provide a patient with the cellular reprogramming therapy and the anti-cancer therapy within about 12 to 24 or 72 h of each other and, more particularly, within about 6-12 h of each other. In some situations it may be desirable to extend the time period for treatment significantly where several days (2, 3, 4, 5, 6, or 7) to several weeks (1, 2, 3, 4, 5, 6, 7, or 8) lapse between respective administrations.

[0271] Various combinations may be employed. For the example below an immune cell therapy is “A” and an anti-cancer therapy is “B”:A / B / A B / A / B B / B / A A / A / B A / B / B B / A / A A / B / B / B B / A / B / BB / B / B / A B / B / A / B A / A / B / B A / B / A / B A / B / B / A B / B / A / AB / A / B / A B / A / A / B A / A / A / B B / A / A / A A / B / A / A A / A / B / A

[0272] Administration of any compound or therapy of the present embodiments to a patient will follow general protocols for the administration of such compounds, taking into account the toxicity, if any, of the agents. Therefore, in some embodiments there is a step of monitoring toxicity that is attributable to combination therapy.IV. Articles of Manufacture or Kits

[0273] An article of manufacture or a kit is provided comprising cellular reprogramming compositions of the disclosure and / or one or more reagents for generating them. The compositions may be from any source. In general embodiments, the reagents may comprise nucleic acid including DNA or RNA, primers, protein, media, buffers, salts, cofactors, and so forth.

[0274] The article of manufacture or kit can further comprise a package insert comprising instructions for using the immune cells to treat or delay progression of cancer in an individual or to enhance immune function of an individual having cancer. Any of the antigenspecific immune cells described herein may be included in the article of manufacture or kits. Suitable containers include, for example, bottles, vials, bags and syringes. The container may be formed from a variety of materials such as glass, plastic (such as polyvinyl chloride or polyolefin), or metal alloy (such as stainless steel or hastelloy). In some embodiments, the container holds the formulation and the label on, or associated with, the container may indicate directions for use. The article of manufacture or kit may further include other materials301645057.1desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. In some embodiments, the article of manufacture further includes one or more of another agent (e.g., a chemotherapeutic agent, and anti-neoplastic agent). Suitable containers for the one or more agent include, for example, bottles, vials, bags and syringes.V. Examples

[0275] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.EXAMPLE 1

[0276] By coupling immune stimulation with immune suppression in a single chain biologic, a therapeutic solution that can be tuned at multiple scales, providing a diseasespecific immune re-engagement that can be refined based on cellular localization, biologically relevant immune cell states or subsets, pharmacokinetics and pharmacodynamics, and to fit within existing treatment paradigms, was engineered. Unlike the current therapeutic discovery model that relies on a single target identification and de novo generation of individual antibodies or small molecule drugs, both of which are time and labor intensive, a library of biologies (>7200 for a single orientation) can be rapidly screened for the appropriately balanced modulation of innate and adaptive immunity. Key indications for these engineered proteins include: suppressing irAEs associated with cancer immunotherapy including fibrosis, suppressing irAEs associated with cancer cell therapies (CAR-T, etc.), targeting immunosenescence to improve cancer vaccine and general vaccine efficacy, treating inflammation-driven diseases (e.g., MASH, NASH, SLE, psoriasis, RA, etc.), treating GVHD in AML, treating or preventing radiation induced fibrosis, inflammatory cardiovascular, and inflammatory neurodegenerative diseases.Example Library Design301645057.1

[0277] The example platform technology was designed to have multiple layers of modularity, where each module could uniquely contribute to the efficacy in a given indication. The library consists of three domains consisting of an Fc domain and two additional immunomodulatory domains enabling the first layer of combinatorial diversity (FIG. 2). One point of novelty of the library relates to the design wherein the linked immuno-modulatory domains are unconstrained from conventional immunological protein topology.Expansion of Library

[0278] Utilizing a machine learning approach, the diversity of the library in the single Fc-X-“B”-“C” permutation was sampled to identify divergent and orthogonal constructs from the initial protein construct PI-1-4-2 (IgGl Fc-4IgB7H3-2IgB7H3 — Human IgGl Fc — B:4Ig-B7-H3 Extracellular domain AA Gly 27 - Thr 461 — C:2Ig-B7-H3 Extracellular domain AA Leu 29 - Pro 245 — (Fig. 4; SEQ ID NO: 1). This construct is also known as PI- 1-4-2 or PI142.

[0279] Each member of the library was represented as a vector (LV) containing the known activation or inhibitor activity or neutrality of a domain (1,-1, or 0 respectively) and a dimensionally reduced representation of the sequence and associated amino acid charge, polarity, and rarity. This virtual library only included the Fc-B-C modules. The Fc domains were also characterized by their steady state plasma levels and known multimerization states of their antibody isotype. A unit vector for each member of the library was created through standardization at each element based upon the library and then normalization of its “length”.

[0280] A model of cost-effective sampling of this large library was to identify the most divergent constructs from the first compound PI- 1-4-2. Starting with PI- 1-4-2 the dot product of LVx with LV(PI- 1-4-2) was created to build a correlation vector CV for each construct. In the case of the first new construct the number of elements in CV was one. The vector closest to 0 using L2 distance was selected e.g. the most orthogonal or most different construct. The most opposite construct may be the construct closest to -1 that may also be tested. This process was then iteratively repeated. The number of elements in CV growing and equaled the number of previously selected constructs. For example, to select the third construct, there were two elements in CV. Each element contained the dot product of the unit vector descriptor of a construct with each of the previously selected constructs. In each round the construct closest (L2 distance) to the null vector was selected. Indeed, this algorithm301645057.1rapidly identified constructs that sampled a diversity of Fc domains (e.g. IgE, IgA, IgD), non-B7 Ig family members (eg HLA-B), and cytokines (IL15). Examination of the correlation matrix indicated that the majority of the low correlation occurred in the first ~ 10 constructs, with higher stochastic correlations as additional members of the library were selected.

[0281] This collection of vectors was further dimensionally reduced for visualization (Mathematica) (FIG. 3).

[0282] This led to generating an expanded library which included constructs that were most “divergent”, additional constructs that provided alternative immune activation and inhibition strategies with a biological context in mind and those that iterated on the lead compound, PI- 1-4-2, by providing point mutations in the IgGl-Fc region with known biological inhibitory or activating potential, and the circular permutation of the construct.301645057.1

[0283] Table 1: Expanded Library of Constructs generated.

[0284] As proof-of-concept and reduction to practice, cloning, protein expression and purification were achieved for all members of the expanded library in Table 1.301645057.1

[0285] Many members of cellular reprogramming protein library constructs and recombinant biologies were synthesized across a diversity of Ig domains and Fc domains, which were successfully produced and characterized by SDS-PAGE and size exclusion HPLC. Using multiple in vitro assays and importantly, in vivo murine models to demonstrate the power of restoring immune homeostasis across multiple therapeutic indications, multiple combinations, including PI- 1-4-2 (SEQ ID NO:1), were identified. The findings demonstrated the ability to rebalance the inflammatory state to promote resolution of chronic and dysregulated inflammation. PI- 1-4-2 demonstrated selective inhibition of respiratory burst compared with bactericidal toxicity, rendering a favorable therapeutic window and showed efficacy in two distinct murine models of inflammation. Using a humanized model of hemophagocytic lymphohistiocytosis (HLH), PI- 1-4-2 treatment twice weekly for two weeks resulted in a significant decrease in neural inflammation and importantly, significantly prolonged survival for these animals. In the second in vivo model, PI- 1-4-2 reduced liver fibrosis in a model of diet-induced nonalcoholic steatohepatitis (NASH), along with modification of diet in aged animals. In both cases a rebalance of the immune dysregulation resulted in favorable outcomes.EXAMPLE 2

[0286] PI-1-4-2, representing IgGl-4IgB7H3- 2IgB7H3, was cloned and characterized (FIG. 4). Upon cloning and production, biochemical characterization of PI- 1-4-2 was performed by SDS-PAGE gel electrophoresis (FIG. 5) and size exclusion chromatography (SEC) (FIG. 6). Additional biologies were generated and included PI-2-2-PDL2, representing IgG2-2IgB7H3-PDL2, which was also characterized (FIGS. 7-9).Library-found biologies can reduce RONS bursts in vitro

[0287] RONS bursts are a key mediator of activated innate immunity and can be monitored using L-012 bioluminescence imaging (BLI). Respiratory bursts (oxidative bursts) resulting in rapid local production of high energy reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important biochemical mediators of activated innate immunity. These reactive respiratory bursts are carried out by many innate immune cells, including neutrophils, eosinophils and macrophages, providing an essential killing mechanism for destruction of intruding pathogens, and can be monitored through bioluminescence using L-012 sodium salt.301645057.1

[0288] Using THP-1 macrophage-like cells polarized into an Ml state (LPS + IFNy), robust oxidative bursts were measured using the bioluminescent substrate L-012, a validated optical reporter of RONS activity under these conditions. Upon PMA activation of polarized THP-1 cells, RONS bursts were measured following vehicle control or pre-treatment with various library found biologies for 60 minutes. Other related commercial reagents (Fc-4Ig-B7H3 ECD, Fc-2Ig-B7H3 (murine) ECD) were also tested that provide B7 domains that can be readily incorporated into the novel scaffolds. A clear dose-dependent decrease in oxidative bursts was observed in the presence of the B7 library biologies (FIG. 10).Pre-Treatment for 4-24 hours with PI- 1-4-2 maintains superior macrophage killing of Salmonella compared to abatacept or dexamethasone.

[0289] The ability for potent anti-inflammatories to calm immune responses while maintaining their anti-fungal, anti-viral, and anti-bacterial function is critical for long term systemic use, especially in the context of use to abate cancer immunotherapy-induced toxicides. To assess the impact of the library found and other competing anti-inflammatories on the ability to maintain bacterial-killing properties of THP-1 macrophage-like cells, molecular imaging and genetically modified bioluminescent bacteria were used to temporally monitor bacteria in co-culture with macrophage-like THP-1 cells. A conventional bacterial killing assay was employed, whereby THP-1 macrophage-like cells were co-cultured with Salmonella engineered to constitutively express the ABCDE Lux operon to produce steady state emitted bioluminescence. Thus, quantification of live Salmonella could be measured over time by monitoring bioluminescence. Non-polarized THP-1 cells were pre-incubated with 30 pM PI- 1-4-2, Fc-CTLA4 (abatacept), and dexamethasone for 4-24 hours prior to the addition of bioluminescent Salmonella. The genetically engineered Salmonella strain (FL6) was grown in 5 mL LB broth at 37°C with gentle agitation for 4 hours until the optical density (OD600) reached 0.45-0.55 and the bacteria were in log growth phase. Bacteria were diluted 5-fold and 15 uL were added to the 96- well plate containing THP-1 cells pre-treated (4-24 hrs) with antiinflammatory biologies, or control diluent. Bioluminescence was measured every 5 minutes over a 30-minute time period using a CCD camera (IVIS Spectrum) at FOV =C, binning 8, exposure 5 seconds. Intracellular and extracellular Salmonella were quantified using the photon flux (p / s) within a designated ROI for each well of the plate. Following the initial 30-minute co-incubation (intracellular + extracellular Salmonella), the plate was spun down, washed and301645057.1re-imaged for an additional 30-minutes, captured every 5 minutes to quantify intracellular bacteria. In both instances (intracellular + extracellular, or intracellular alone), PI- 1-4-2 slightly enhanced bacterial killing by THP-1 cells (-3-21%) as compared to PBS treatment alone. Importantly, this effect was not observed with abatacept or dexamethasone, wherein the number of bacteria remaining was greater than no-treatment or diluent treatment alone, consistent with a blunting of the anti-bacterial efficacy of THP-1 cells with 4 hour or 24 hour pre-treatment with these conventional anti-inflammatories (FIGS. 11A-11D). This indicated the superiority of PI- 1-4-2 to maintain anti-bacterial activity of THP-1 macrophage-like cells as compared to pre-treatment with abatacept or dexamethasone. The treatment with PI- 1-4-2 was significantly different than treatment with the other anti-inflammatories (abatacept or dexamethasone) suggesting superiority in the capacity to maintain bacterial killing efficacy of THP-1 cells.

[0290] Overall, the results indicated that PI 1-4-2 shows selectivity for inhibition of respiratory burst vs bactericidal activity.Library-found biologies reduce RONS bursts \n vivo

[0291] The results were first extended to a humanized mouse model of neuroinflammation, i.e., hemophagocytic lymphohistiocytosis (HLH), a model that also captures features of a CAR-T cell-induced neuro-inflammation syndrome known as immune cell-associated neurological syndrome (ICANS). CD34+ hu-SGM3 mice were used to model HLH, wherein basal RONS bursts can be directly observed in the cranial cavity following administration of L-012 and bioluminescence imaging (BLI). Hu-CD34+ NSG-SGM3 are NSG-SGM3 mice (NOD.Cg-Prkdcscid I12rgtmlWjl Tg(CMV-IL3, CSF2, KITLG)lEav / MloySzJ, Stock No. 013062) engrafted with human cord blood-derived CD34+ hematopoietic stem cells. NSG-SGM3 mice combine the features of the highly immunodeficient NOD SCID gamma (NSG) mouse platform with transgenic expression of human IL3, GM-CSF (CSF2) and SCF (KITLG) cytokines for improved development of human myeloid lineages and regulatory T-cell populations. hu-CD34+ NSG-SGM3 mice exhibit superior, stable engraftment of diverse hematopoietic lineages for immunology and immuno-oncology research. Herein, weekly treatment with B PL 1-4-2 (200 pg) significantly reduced the cranial L-012 signal as a signature of reduced inflammation (FIG. 12). L-012 cranial signal remained near baseline in PBS-treated mice, while PLl-4-2-treated mice showed301645057.1a significant decrease in RONS bursts. Furthermore, the cranial RONS bursts remained low following the end of treatment.

[0292] A second in vivo study was performed using a larger cohort of mice, where long term survival was monitored following two weeks of PI- 1-4-2 treatment (FIG. 14).Importantly, this phenotype was re-capitulated when looking at RONS bursts of patient PBMCs, where the patient who had refractory diffuse large B-cell lymphoma treated with Axicel developed ICANS and HLH. Conventional treatment with steroids and anakinra was started and PBMCs were collected for detection of RONS bursts. Treatment of PBMCs from the patient with 20 nM PI- 1-4-2 showed a time dependent decrease in RONS bursts that was superior to the change in cell viability observed at 24 hours post treatment and ex- vivo culture of the primary PBMCs (FIGS. 15A-15D).

[0293] To assess the impact of PI- 1-4-2 on a second model of inflammation-driven disease, a murine model of diet-induced non-alcoholic steatohepatitis (NASH) was used. C57BL / 6NTac mice were obtained from Taconic, having been fed a modified Amylin liver NASH diet containing 40 kcal% fat, 20 kcal% fructose and 2% cholesterol from 6 weeks of age. By 26 weeks of age, mice are well characterized to become obese, develop a fatty liver, and develop liver inflammation and fibrosis. For this study, mice were returned to normal diet at 40 weeks of age, where some resolution of liver fibrosis can be observed with the corrective behavioral action. Mice were then treated with PBS or PI- 1-4-2 (200 pg) once weekly, by i.p, injection for 8 weeks. Weight was monitored weekly, and endpoint analysis was performed for each mouse liver, specifically measuring RONS bursts, fibrosis as determined by PicroSirius red, and fat deposits as observed with H&E staining. Importantly, PI- 1-4-2 significantly reduced the PicroSirius red positive fibrotic staining and reduced the appearance of fat deposits, which was also represented by an increase in the liver pseudo density (liver weight / area (FIG.13). F4 / 80 hepatic-crown-like structures (hCLS), indicative of inflammation and fibrosis during the progression of NASH (FIGS. 16A-16E), showed significant reductions with PI-1-4-2 treatment compared to PBS-treated control animals.

[0294] Thus, in summary, PI- 1-4-2 demonstrated the power of the library designed to return a system to homeostasis through subtle tuning of the immune system vs. potent inhibitors and activators of the acute phase both in vivo and in cellulo while derisking manufacturability through the use of immunomodulatory Ig domains and small cytokines (FIG. 18).301645057.1EXAMPLE 3

[0295] Cloning and characterizing additional immunomodulating protein examples are shown herein.

[0296] FIG. 19 shows the amino acid sequence of IgE_2Ig-B7-H3_IL15. IgE_2Ig-B7-H3_IL15 was cloned and biochemical characterization was performed by SDS-PAGE (FIG. 20) and SEC (FIG. 21).

[0297] FIG. 22 shows the amino acid sequence of IgA-HLA-F-CD4. IgA-HLA-F-CD4 was cloned and biochemical characterization was performed by SDS-PAGE (FIG. 23), Western blot (FIG. 24), and SEC (FIG. 25).

[0298] FIG. 26 shows the amino acid sequence of IgM-CD19-CD4. IgM-CD19-CD4 was cloned and biochemical characterization was performed by SDS-PAGE (FIG.27), Western blot (FIG. 28), and SEC (FIG. 29).

[0299] FIG. 30 shows the amino acid sequence of IgE-HLA-B-B7-H4 (VTCN1). IgE-HLA-B-B7-H4 (VTCN1) was cloned and biochemical characterization was performed by SDS-PAGE (FIG. 31), Western blot (FIG. 32), and SEC (FIG. 33).

[0300] FIG. 34 shows the amino acid sequence of IgD-HLA-B-CD80. IgD-HLA-B-CD80 was cloned and biochemical characterization was performed by SDS-PAGE (FIG. 35) and SEC (FIG. 36).

[0301] FIG. 37 shows the amino acid sequence of IgG3-IL25-CD274. IgG3-IL25-CD274 was cloned and biochemical characterization was performed by SDS-PAGE (FIG. 38) and SEC (FIG. 39).

[0302] FIG. 40 shows the amino acid sequence of IgE-TNFa-TGF-B. IgE-TNFa-TGF-B was cloned and biochemical characterization was performed by SDS-PAGE (FIG. 41), Western blot (FIG. 42), and SEC (FIG. 43).

[0303] FIG. 44 shows the amino acid sequence of IgA-IL-15-IL-17RB. IgA-IL-15-IL-17RB was cloned and biochemical characterization was performed by SDS-PAGE (FIG. 45), Western blot (FIG. 46), and SEC (FIG. 47).301645057.1

[0304] FIG. 48 shows the amino acid sequence of IgGl-Act-4Ig B7-H3-2Ig-B7-H3. IgGl-Act-4Ig B7-H3-2Ig-B7-H3 was cloned and biochemical characterization was performed by SDS-PAGE (FIG. 49) and SEC (FIG. 50). FIG. 51 shows a schematic of IgGl-Act-4Ig B7-H3-2Ig-B7-H3.

[0305] FIG. 52 shows the amino acid sequence of IgGl- LALA-4Ig B7-H3-2Ig-B7-H3. IgGl- LALA-4Ig B7-H3-2Ig-B7-H3 was cloned and biochemical characterization was performed by SDS-PAGE (FIG. 53) and SEC (FIG. 54). FIG. 55 shows a schematic of IgGl- LALA-4Ig B7-H3-2Ig-B7-H3.

[0306] FIG. 56 shows the amino acid sequence of 4IgB7-H3-IgGl-2Ig-B7-H3.4IgB7-H3-IgGl-2Ig-B7-H3 was cloned and biochemical characterization was performed by SDS-PAGE (FIG. 57) and SEC (FIG. 58). FIG. 59 shows a schematic of 4IgB7-H3-IgGl-2Ig-B7-H3.

[0307] FIG. 60 shows the amino acid sequence of 4Ig-B7-H3_2Ig-B7-H3_IgGl. 4Ig-B7-H3_2Ig-B7-H3_IgGl was cloned and biochemical characterization was performed by SDS-PAGE (FIG. 61) and SEC (FIG. 62). FIG. 63 shows a schematic of 41g-B7-H3_2Ig-B7-H3_IgGl.Ml-polarized macrophages exhibited RONS bursts upon PMA activation, which can be inhibited by Pl-constructs.

[0308] As shown in FIGS. 64-65, PI- 1-4-2 and PI-2-2-PDL2 inhibited RONS bursts of Ml-polarized primary macrophages, confirming previously observed phenotypes using polarized THP-1 Ml-like cells.

[0309] M2c-polarized macrophages, which are only modestly stimulated by PMA, can be further activated and increase RONS bursts with the addition of selective PI constructs. FIGS. 66-67 show that the new proteins which were identified (PI-E-2-15 and PI-3-25-274) were capable of increasing RONS bursts of M2c-polarized primary human macrophages.301645057.1Circularly permutated PI constructs have differential functions on Ml- or M2-polarized primary human macrophages.

[0310] FIG. 68 shows schematics of PI- 1-4-2, PI-4-1-2, and PI-4-2-1. FIG.69 shows relative total flux over M2 polarization. These results suggested that Fc-location and order of the protein modules impact PI function, and the standard antibody topography do not allow circular permutation of interacting domains.EXAMPLE 4

[0311] Cloning and characterizing for additional immunomodulating protein examples are shown in Figs. 73-100. Amino acid sequences, protein production and biochemical characterization was performed for additional members of the library including PI-1-PDCD-IL37, PI-lAct-25-B2M, PI-4-CD19-HLAB, PI-2-2-HLAF-1, PI-1LALA-HLAF1-CD80, PI-1-HLAB-CD86, PI-2-CD19-CD86, PI-3-CD4-CD8A, and PI-2-4-HLAC, (SEQ ID Nos: 15-23) demonstrating robust activity of a diversified protein construct library featuring multiple Fc domain architectures with and without engineered mutations, along with distinct size variants and interchangeable B- and C- module domain-swapped configurations (Figs. 101-130). Additional clones were synthesized with appended proteins cMMP-Semi, GLP-1, and GIP (Figs. 133-141; SEQ ID NOs: 14-26, respectively).* * *

[0312] All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.301645057.1

Claims

WHAT IS CLAIMED IS:

1. A cellular reprogramming protein comprising, in order, a first polypeptide, a second polypeptide, and a third polypeptide, wherein the first polypeptide, second polypeptide, and third polypeptide are selected from the group consisting of Human Fc domain, B7 protein, CD80, CD83, CD86, ICOS, MHC-I, MHC-II, CD40, IL- 18, IL-37, TNF-alpha, INF-gamma, cytokines, IL-15, HLA-F, CD19, CD4, HLA-B, IL- 17RB, and TGF-beta, and wherein the cellular reprogramming protein comprises exactly one human Fc domain.

2. The cellular reprogramming protein of claim 1, wherein the human Fc domain is IgE, IgA, IgM, IgE, IgD, IgG3, IgE, IgA, IgGl-Act, IgGl-LALA, or IgGl.

3. The cellular reprogramming protein of any one of claims 1 or 2, wherein the B7 protein is B7-H3, B7-H2, B7-DC, B7-H4, B7-H6, or B7-H7.

4. The cellular reprogramming protein of any one of claims 1 to 3, wherein the Fc domain comprises an activating mutant or an inhibitory mutant.

5. The cellular reprogramming protein of any one of claims 1 to 4, wherein the protein comprises a first linker sequence of amino acids between the first polypeptide and the second polypeptide, and wherein the protein comprises a second linker sequence of amino acids between the second polypeptide and the third polypeptide.

6. The cellular reprogramming protein of claim 5, wherein the first linker sequence and / or the second linker sequence comprises the amino acid sequence GGGSx4.

7. The cellular reprogramming protein of any one of claims 1 to 5, wherein the first polypeptide is IgGl, the second polypeptide is 41g-B7H3, and the third polypeptide is 21g-B7H3.

8. The cellular reprogramming protein of claim 1, wherein the protein is at least 80% similar to SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 without a signaling peptide.301645057.

19. The cellular reprogramming protein of any one of claims 1-5, wherein the first polypeptide is IgE, the second polypeptide is 21g-B7-H3, and the third polypeptide is IL15.

10. The cellular reprogramming protein of any one of claims 1-5, wherein the first polypeptide is IgA, the second polypeptide is HLA-F, and the third polypeptide is CD4.

11. The cellular reprogramming protein of any one of claims 1-5, wherein the first polypeptide is IgM, the second polypeptide is CD 19, and the third polypeptide is CD4.

12. The cellular reprogramming protein of any one of claims 1-5, wherein the first polypeptide is IgE, the second polypeptide is HLA-B, and the third polypeptide is B7- H4 (VTCN1).

13. The cellular reprogramming protein of any one of claims 1-5, wherein the first polypeptide is IgD, the second polypeptide is HLA-B, and the third polypeptide is CD80.

14. The cellular reprogramming protein of any one of claims 1-5, wherein the first polypeptide is IgG3, the second polypeptide is IL25, and the third polypeptide is CD274.

15. The cellular reprogramming protein reprogramming protein of any one of claims 1-5, wherein the first polypeptide is IgE, the second polypeptide is TNFa, and the third polypeptide is TFG-B.

16. The cellular reprogramming protein of any one of claims 1-5, wherein the first polypeptide is IgA, the second polypeptide is IL- 15, and the third polypeptide is IL- 17RB.

17. The cellular reprogramming protein of any one of claims 1-5, wherein the first polypeptide is IgGl-Act, the second polypeptide is 41g B7-H3, and the third polypeptide is 21g-B7-H3.301645057.

118. The cellular reprogramming protein of any one of claims 1-5, wherein the first polypeptide is IgGl-LALA, the second polypeptide is 41g B7-H3, and the third polypeptide is 21g-B7-H3.

19. The cellular reprogramming protein of any one of claims 1-5, wherein the first polypeptide is 41g B7-H3, the second polypeptide is IgGl, and the third polypeptide is 21g-B7-H3.

20. The cellular reprogramming protein of any one of claims 1-5, wherein the first polypeptide is 41g B7-H3, the second polypeptide is 21g-B7-H3, and the third polypeptide is IgGl.

21. The cellular reprogramming protein of any one of claims 1-20, wherein the cellular reprogramming protein additionally comprises one or more a small molecule toxin, immunostimulant, p28 (azurin fragment), Flagellin and derivatives, Ac SDKP, Humanin, MOTS c, LL 37, C peptide fragment, Thymosin P4 fragment, GLP1, GIP, GLP 2 fragment, Apelin 13, KPV, VIP fragment, Uroguanylin fragment, Kisspeptin 10, PTH(1-14), BDNF mimetic GSB 106, GHK Cu, Melanotan II fragment, Thymosin al fragment, a MSH KPV, Defensin fragment, Thymosin p4(l-4), NPY13 36, Endomorphin 1, and / or Histatin 5 fragment on an end terminus.

22. The cellular reprogramming protein of any one of claims 1-21, further comprising a bifunctional chelate.

23. A nucleic acid molecule comprising a nucleotide sequence encoding a protein as defined in any one of claims 1-22.

24. A method of modulating or imaging cellular processes in an individual comprising administering to the individual the protein of any one of claims 1-22 or the nucleic acid of claim 23.

25. The method of claim 24, wherein the individual has been previously treated for cancer.

26. The method of claims 24 or 25, wherein the individual has inflammation, lymphedema, fibrosis, Castleman disease, and / or lymphatic dysfunction.301645057.

127. A computer implemented method of identifying a cellular reprogramming protein that reprograms the cellular processes of an individual in need thereof comprising:generating a set of protein sequences comprising in order, a first polypeptide, a second polypeptide, and a third polypeptide, wherein the first polypeptide, second polypeptide, and third polypeptide are selected from the group consisting of Human Fc domain, B7 protein, CD80, CD83, CD86, ICOS, MHC-I, MHC-II, CD40, IL- 18, IL-37, TNF-alpha, INF-gamma, cytokines, IL-15, HLA-F, CD19, CD4, HLA-B, IL- 17RB, and TGF-beta, and wherein the immunomodulating polypeptide comprises exactly one human Fc domain;generating a protein with a sequence from the at least one of the set of protein sequences;testing the generated protein for activity.

28. A computer implemented method for producing cellular reprogramming proteins using an analytics module executed by a processor of a computer system, the method comprising:receiving, by the analytics module from a computer data storage system, at least one Fc domain identifier and a plurality of extracellular polypeptide identifiers;sampling, by the analytics module executed by the processor, constructs comprising at least one of the identified Fc domains and at least two of the identified polypeptides, for each sampled construct calculate if it is orthogonal or divergent;transmitting at least one of the constructs to a machine, wherein the at least one selected construct is selected based on its orthogonality;creating a synthetic protein with the selected sequence.

29. The method of claim 28, wherein the synthetic protein is tested for immune modulation.

30. The method of claim 29, wherein the synthetic protein is tested for anti-inflammatory properties.301645057.

131. The method of claim 29, wherein the synthetic protein is tested for cellular response to cancer, fibrosis, neurodegeneration, deconditioning, viral latency and reactivation, metabolic dysfunction, barrier dysfunction, digestive disorders, cardiovascular disease, wound healing, respiratory disease, urinary and excretory system disorders, infertility, osteoporosis and fracture, hearing loss, cosmetic applications, sexual dysfunction, immunosenescence, chronic and recurrent infectious diseases, regenerative and transplant medicine, psychosis disorders, chronic pain, autoimmune disease, and microbial response.

32. The method of any one of claims 28-31, wherein the synthetic protein comprise a plurality of sequences with, in order, a first polypeptide, a second polypeptide, and a third polypeptide, wherein the first polypeptide, second polypeptide, and third polypeptide are selected from the group consisting of Human Fc domain, B7 protein, CD80, CD83, CD86, ICOS, MHC-I, MHC-II, CD40, IL- 18, IL-37, TNF-alpha, INF- gamma, cytokines, IL-15, HLA-F, CD19, CD4, HLA-B, IL-17RB, and TGF-beta, and wherein each protein sequence comprises exactly one human Fc domain.

33. The method of any one of claims 28-32, wherein the synthetic protein is created using recombinant protein expression.

34. The method of claim 33, wherein the recombinant protein expression is automated from receipt of the selected sequence.

35. The method of any one of claims 28-32, wherein the synthetic protein is created using solid-phase peptide synthesis.

36. The method of claim 35, wherein the solid-phase peptide synthesis is automated from receipt of the transmitted selected sequence.

37. The method of any one of claims 28-26, wherein sampling comprises a machine learning method.

38. A non-transitory computer-readable storage medium having computer-executable instructions stored thereon, which when executed by one or more processors, causes the one or more processors to perform operations comprising:301645057.1(a) receiving at least one Fc domain identifier and a plurality of extracellular polypeptide identifiers;(b) sample constructs comprising one Fc domain and at least two polypeptides;(c) for each sample construct, calculating if it is orthogonal or divergent;(d) transmitting at least one construct, wherein the construct is selected based orthogonality.

39. The storage medium of claim 38, wherein sampling and / or calculating comprises a machine learning method.

40. The storage medium of claim 38 or 39, wherein the set of protein sequences comprises a plurality of sequences with, in order, a first polypeptide, a second polypeptide, and a third polypeptide, wherein the first polypeptide, second polypeptide, and third polypeptide are selected from the group consisting of Human Fc domain, B7 protein, CD80, CD83, CD86, ICOS, MHC-I, MHC-II, CD40, IL- 18, IL-37, TNF-alpha, INF-gamma, cytokines, IL-15, HLA-F, CD19, CD4, HLA-B, IL- 17RB, and TGF-beta, and wherein each protein sequence comprises exactly one human Fc domain.

41. The storage medium of any one of claims 38-40, wherein the calculating is based on a dimensionally reduced representation of the sequence and associated amino acid charge, polarity, rarity, hydrophobicity, steady state plasma levels, and / or known multimerization states of their antibody isotype.

42. The storage medium of any one of claims 38-41, wherein a ranked order of orthogonally identified constructs is transmitted.

43. The storage medium of any one of claims 38-42, wherein the Fc domain identifiers and / or the extracellular polypeptide identifiers are identified by name and / or sequence.

44. A method of modulating or imaging cellular processes in an individual comprising administering to the individual the protein of any one of claims 1-22 or the nucleic acid of claim 23.301645057.

145. The method of claim 24, wherein the individual has cancer, neurodegeneration, deconditioning, viral latency and reactivation, metabolic dysfunction, barrier dysfunction, digestive disorders, cardiovascular disease, wound healing, respiratory disease, urinary and excretory system disorders, infertility, osteoporosis and fracture, hearing loss, cosmetic applications, sexual dysfunction, immunosenescence, chronic and recurrent infectious diseases, regenerative and transplant medicine, psychosis disorders, chronic pain, autoimmune disease, and microbial response301645057.1

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