36 results about "Genetically modified mouse" patented technology

The invention discloses a construction method of a conditional knock-down dynactin animal model of astrocytes and an application of the animal model of the conditional knock-down dynactin animal model of the astrocytes. According to the method, a Dctn1LoxP gene knock-in mouse is hybridized with an Aldh1l1-Cre / ERT2 transgenic mouse, a target genotype mouse is obtained through three rounds of breeding, 100mg / kg Tamoxifen is continuously injected into the intraperitoneal cavity of the 2-month-old mouse for 5 days, and specific knock-down of dynactin in brain and spinal astrocytes is realized, including knockout of p150Glue and reduction of DCTN4, p50 and Arp1alpha protein levels. The model has the advantages of being high in specificity, permanent in intervention aging and capable of covering multiple life stages, the defects of a traditional model are overcome, the model can be used for researching the influence of dynactin on astrocyte neurobiological functions, a reliable tool is provided for screening related targets of nervous system diseases, and the model has important application value.

Genetically modified mice whose immunoglobulin loci are engineered to be inserted into gene segments of human immunoglobulin variable regions are disclosed, the mice being capable of normal reproduction and producing human-mouse chimeric antibodies comprising a human variable region and a mouse constant region. The invention also provides a method for preparing the genetically modified mouse and application of the mouse.

Genetically modified non-human animals and methods and compositions for making and using them are provided, wherein the genetic modification comprises a deletion in an immunoglobulin constant region CH1 gene (optionally a deletion in a hinge region) of an IgG, IgA, IgD, and / or IgE, and wherein the mouse is capable of expressing a functional IgM. Genetically modified mice are described, including mice having a functional IgM gene and modified to have a deletion of a CH1 domain and a hinge region in a heavy chain constant domain that is not an IgM, e.g., in an IgG heavy chain constant domain. Genetically modified mice that make human variable / mouse constant chimeric heavy chain antibodies (antibodies that lack a light chain), fully mouse heavy chain antibodies, or fully human heavy chain antibodies are provided.

The invention discloses a construction method of an endothelial cell knockout Cdc42 gene aggravated bleomycin induced pulmonary fibrosis mouse model, which comprises the following steps of: mating a Cdc42 gene conditional knockout mouse with a mouse (Tie2-CreER) of which the endothelial cell specifically expresses tamoxifen induced Cre recombinase to obtain a double-transgenic mouse (Cdc42fl / fl-Tie2-CreER); the Cdc42 gene is specifically knocked out in vascular endothelial cells under the induction of tamoxifen, and then pulmonary fibrosis is induced by subcutaneous injection of bleomycin. The model shows aggravated pulmonary fibrosis phenotypes, including collagen deposition increase, alveolar structure damage and fibrosis-related protein expression up-regulation, and is high in construction success rate and good in repeatability. The invention also provides an application of the model in research of systemic sclerosis related interstitial lung disease pathogenesis and screening of anti-pulmonary fibrosis drugs, and an application of the Cdc42 gene as a drug target, and provides an accurate and reliable tool for pulmonary fibrosis research.

A genetically modified mouse is provided, wherein the mouse is incapable of rearranging and expressing an endogenous mouse immunoglobulin light chain variable sequence, wherein the mouse expresses only one or two human light chain variable domains encoded by human immunoglobulin sequences operably linked to the mouse kappa (κ) constant gene at the endogenous mouse κ locus, wherein the mouse expresses a reverse chimeric antibody having a light chain variable domain derived from one of only two human light chain variable region gene segments and a mouse κ constant domain, and a human heavy chain variable domain and a mouse heavy chain constant domain, from an endogenous mouse heavy chain locus. Bispecific epitope-binding proteins that are fully human are provided, comprising two different heavy chains that associate with an identical light chain that comprises a variable domain derived from one of two different human light chain variable region gene segments.

Chimeric transgenic immunoglobulin (Ig) mice comprising altered heavy chain loci are provided in which endogenous mouse D and J segments have been deleted and at which a human heavy chain Ig transgene is inserted, such that the transgenic Ig mice express an antibody library that utilizes human VH and mouse VH in the heavy chain, each linked to human DH and JH segments, thus, enhanced diversity is produced. Methods of making and using transgenic animals (e.g., to produce antibodies) are also provided.

The invention provides a preparation method of a genetically modified mouse capable of mediating Tbx1 inherent disorder protein structural domain deletion. The method comprises the following steps: (a) constructing a targeting vector; (b) preparing a gene editing compound; (c) microinjection; (d) embryo transplantation and screening; (e) breeding and establishing a stable strain. Sequencing verifies that the gene modified mouse can stably express the Tbx1 mutant protein which lacks IDR and carries an N-terminal 3xFlag tag, and a homozygote mutant mouse shows remarkable developmental defects such as ventricular septal defect and craniofacial deformity; and an important genetic tool is provided for researching the action mechanism of the phase separation characteristic of the Tbx1 protein in the heart, craniofacial development and congenital heart disease (such as DiGeorge syndrome).

Disclosed in the present disclosure is genetically modified mice in which immunoglobulin loci are modified to insert gene segments of a human immunoglobulin variable region. The mice can be bred normally and produce human-mouse chimeric antibodies including a human variable region and a mouse constant region. The present disclosure also provides a method for preparing the genetically modified mice and use of the mice.

Bag3 is a multifunctional protein expressed predominantly in the heart, the skeletal muscle, the central nervous system and in many cancers. Although BAG3 was cloned only a decade ago, studies have shown that genetic variants, particularly those that result in haplo-insufficiency, can lead to severe left ventricular dysfunction; however, the full mechanisms responsible have remained obscure. To obviate the influence of heart failure itself on the biology of Bag3, transgenic mice harboring a single allele knock-out were studied between 8 and 10 weeks of age before any obvious signs of heart failure were evident. The results were surprising and informative. First, it was found that despite a normal phenotype, young Bag3+ / − had marked changes in the proteome that were characterized by changes in proteins associated with metabolism and apoptosis. Consistent with this finding, a decrease in the levels of critical proteins charged with maintaining the mitochondrial membrane potential was observed. It was also found that young mice shifted from a balance between the extrinsic and intrinsic pathways of apoptosis. However, in the presence of stress and the absence of Bag3 there was a shift from a balanced to an extrinsic dominant system (cleaved caspase 8). The diverse array of critical pathways regulated by Bag3 suggests a more important role especially during stress and that this role might include serving as an intracellular glue that holds proteins where they can be most effective rather than having them meet accidentally.

The present invention provides genetically modified animals (e.g., mice), humanized heavy chain antibodies, humanized nanobodies, and methods for producing and using them. [Solution] Provided are genetically modified non-human animals (e.g., genetically modified mice) that can be designed to produce heavy chain antibodies that can be used to generate single-domain antibodies or nanobodies. In one embodiment, a genetically modified mouse is provided comprising a germline modification comprising deletion of nucleic acid sequences comprising one or more heavy chain C region genes; the genetically modified mouse expresses an IgG heavy chain antibody and secretes an IgG heavy chain antibody in its serum.

The application discloses a construction method and application of an NLRP3 humanized mouse model, and belongs to the technical field of genetic engineering. The construction method of the NLRP3 humanized mouse model comprises the step of mutating the 708th amino acid of mouse Nlrp3-201 protein into a non-acidic amino acid; the Ensembl ID of the mouse Nlrp3-201 is ENSMUST00000079476.10. It is verified that the 708th amino acid of the mouse NLRP3 protein is mutated into a non-acidic amino acid (for example, alanine), the NLRP3 of the obtained mutant transgenic mouse is similar to human NLRP3, and cannot be cut by caspase-3, and humanization is realized. The mutant mouse model can better reflect the biological processes such as human inflammasome activation, cell pyroptosis and inflammatory reaction, and provides a more accurate animal model for understanding human diseases and drug screening.

Disclosed in the present disclosure is genetically modified mice in which immunoglobulin loci are modified to insert gene segments of a human immunoglobulin variable region. The mice can be bred normally and produce human-mouse chimeric antibodies including a human variable region and a mouse constant region. The present disclosure also provides a method for preparing the genetically modified mice and use of the mice.

This invention discloses a method for preparing Huangda tea polysaccharide L2-1 and its use in preventing and improving Alzheimer's disease. Huangda tea polysaccharide L2-1 has a total sugar content of 91.89%, a protein content of 1.19%, and a uronic acid content of 13.18%. The monosaccharide composition and its molar ratio are arabinose:rhamnose:mannose:glucose:galacturonic acid = 0.169:0.256:0.464:1:1.396. The Huangda tea polysaccharide L2-1 prepared by this invention can significantly improve the survival rate of L-Glu-induced PC12 cells and restore cell morphology, enhance the learning and memory abilities of APP / PS1 transgenic mice, inhibit the excessive activation of astrocytes in mouse brain tissue, and reduce neuroinflammation in the mouse brain. Huangda tea polysaccharide L2-1 has the function of improving / treating Alzheimer's disease.

A mouse with a humanization of the mIL-3 gene and the mGM-CSF gene, a knockout of a mRAG gene, and a knockout of a mIl2rg subunit gene; and optionally a humanization of the TPO gene is described. A RAG / Il2rg KO / hTPO knock-in mouse is described. A mouse engrafted with human hematopoietic stem cells (HSCs) that maintains a human immune cell (HIC) population derived from the HSCs and that is infectable by a human pathogen, e.g., S. typhi or M. tuberculosis is described. A mouse that models a human pathogen infection that is poorly modeled in mice is described, e.g., a mouse that models a human mycobacterial infection, wherein the mouse develops one or more granulomas comprising human immune cells. A mouse that comprises a human hematopoietic malignancy that originates from an early human hematopoietic cells is described, e.g., a myeloid leukemia or a myeloproliferative neoplasia.

The invention provides a traditional Chinese medicine composition for resisting Alzheimer's disease as well as a preparation method and application of the traditional Chinese medicine composition. The traditional Chinese medicine composition is prepared from the following active ingredients in parts by weight: 6-50 parts of gastrodia elata, 6-50 parts of uncaria rhynchophylla, 9-60 parts of concha haliotidis, 6-50 parts of prepared rehmannia root, 6-50 parts of radix cyathulae, 3-30 parts of semen raphani, 3-30 parts of eucommia ulmoides, 3-30 parts of parasitic loranthus, 3-30 parts of scutellaria baicalensis, 3-30 parts of herba lycopi, 3-30 parts of vine of multiflower knotweed and 3-30 parts of cinnabar root poria. The raw materials of the medicine are common, the preparation method is simple and easy to operate, the medicine has wide application value, after oral administration of the medicine, cognitive impairment of a transgenic mouse model of the Alzheimer's disease can be obviously improved, deposition of age pigment in brain tissue is reduced, meanwhile, the number of activated microglia and astroglia in the brain tissue is reduced, and the treatment effect of the Alzheimer's disease is improved. The compound inhibits the formation of A beta in brain tissues, and has a new application of anti-Alzheimer's disease drugs.

This document relates to non-human animal models (e.g., non-human mammalian models such as mouse models) for aging (e.g., neural aging). For example, non-human animal models having reduced or eliminated levels of aralkylamine N-acetyltransferase (AANAT) polypeptide expression are provided.

Disclosed herein are non-human animals (e.g., rodents, e.g., mice or rats), the non-human animal is genetically engineered to express a humanized or human T cell receptor (TCR) comprising a variable domain encoded by (a) at least one human TCR variable region gamma gene segment and a (human) TCR gamma constant region gene sequence and / or (b) at least one human TCR variable region delta gene segment and a (human) TCR delta constant region gene sequence. Also provided are embryos, tissues, and cells expressing the receptors. Also provided are methods of making genetically engineered animals expressing the humanized or human gamma and / or delta TCRs. Also provided are methods of developing human therapeutics using the genetically engineered animals that produce a substantially humanized T cell immune response.

The invention belongs to the technical field of biological medicines, and relates to application of cyclin kinase in preparation of medicines for improving stress self-protection disorder related diseases. The invention relates to an application of cyclin kinase (CDK5) in preparation of drugs for improving stress self-protection disorder related diseases. The invention constructs a platycodon grandiflorum / clustered cell specific knockout CDK5 transgenic mouse. Besides, the CDK5 is proved to be capable of effectively reversing nTMT-induced mouse crisis decision disorder from the level of in-vivo electrophysiological neuron population decoding, normal crisis decision and normal expression of the normal crisis decision and multimode neural coding of the normal crisis decision dependent on back-side olfactory bulb / clustered cell CDK5, and an experimental basis is provided for treatment of stress self-protection disorder related diseases by the CDK5.

The invention discloses an application of guanylate binding protein 5 (GBP5) in preparation of a medicine for preventing, relieving or treating cardiac hypertrophy and fibrosis, in particular to a medicine for preventing, relieving or treating cardiac hypertrophy and fibrosis. GBP5 transgenic mice and non-transgenic mice are selected for testing, each mouse is divided into a false operation group and an operation group, aortic arch constriction operation is performed on the operation group, aortic arch constriction is not performed on the false operation group, and then cardiac hypertrophy, fibrosis and cardiac functions of the mice in the false operation group and the operation group are determined, so that the cardiac function of the mice in the false operation group and the operation group is determined. The influence of GBP5 gene overexpression on cardiac hypertrophy induced by aortic arch constriction is researched. Results show that the over-expressed GBP5 gene can significantly inhibit cardiac hypertrophy and fibrosis and protect cardiac functions, so that GBP5 can be used for preparing drugs for preventing, relieving or treating cardiac hypertrophy and fibrosis.

Genetically modified mice and methods for making an using them are provided, wherein the mice comprise a replacement of all or substantially all immunoglobulin heavy chain V gene segments, D gene segments, and J gene segments with at least one light chain V gene segment and at least one light chain J gene segment. Mice that make binding proteins that comprise a light chain variable domain operably linked to a heavy chain constant region are provided. Binding proteins that contain an immunoglobulin light chain variable domain, including a somatically hypermutated light chain variable domain, fused with a heavy chain constant region, are provided. Modified cells, embryos, and mice that encode sequences for making the binding proteins are provided.

The invention relates to a construction and evaluation method of an animal model of Alzheimer's disease spleen and kidney deficiency and phlegm and blood stasis syndrome based on combination of diseases and syndromes, and belongs to the technical field of construction of animal models combined with diseases and syndromes. A double transgenic APP / PS1 mouse is taken as an AD model animal, a standard animal model of AD spleen and kidney deficiency and phlegm and blood stasis syndrome is constructed by adopting high-glucose and high-fat diet feeding in combination with ice-water bath and tail-clamping stimulation intervention, and the model is subjected to'disease-syndrome-prescription-effect 'comprehensive judgment from four dimensions of a modeling method, macroscopic characterization, microscopic characterization and prescription-based test. The method aims to construct a reproducible and standardized animal model with the AD spleen and kidney deficiency and the phlegm and blood stasis syndrome, and a scientific basis is provided for construction of a disease-syndrome-prescription-effect diagnosis and treatment normal form of the AD spleen and kidney deficiency and the phlegm and blood stasis syndrome. Meanwhile, the mold manufactured through the method has the advantages of being high in controllability, small in physical and chemical property stimulation, capable of being copied and verified and the like.

The invention belongs to the technical field of biomedicine, and discloses application of a CHOP gene in preparation of a medicine for treating Alzheimer's disease. According to the application disclosed by the invention, the fact that the beta amyloid deposition of AD can be effectively relieved by knocking out or knocking down the CHOP gene is determined for the first time, neuroinflammation in the brain can be reduced, and the spatial learning and memory ability disorder of AD transgenic mice can be effectively improved. A new target spot is provided for AD treatment, clinical transformation value is achieved, and a preparation with the CHOP gene knocked out or knocked down can be used for preparing the medicine for treating the Alzheimer's disease.

A genetically modified mouse is provided, wherein the mouse expresses a repertoire of immunoglobulin light chains characterized by a limited number of light chain variable domains. Mice are provided that exhibit a selection of two human light chain variable region gene segments, such that the immunoglobulin light chains expressed by the mouse comprise one of the two human light chain variable region gene segments. Methods are provided for generating bispecific antibodies having universal light chains using mice described herein, comprising the human light chain variable regions. Methods are provided for generating human variable regions suitable for use in multispecific binding proteins, e.g. bispecific antibodies, as well as host cells.

Relapsing remitting multiple sclerosis (RRMS) is the most common form of multiple sclerosis, affecting more than 80% of MS patients. RRMS is comprised of two phases: the auto-inflammatory episodes, in which the immune system is actively destroying myelin, alternate with remission phases. Currently there is no cure for this devastating disease. The present disclosure provides compositions and methods useful for inducing remyelination. The methods are useful for promoting remyelination to treat diseases and disorders such as MS. The present disclosure describes compositions and methods useful for inhibiting LRP1 activity. In one aspect, a siRNA against LRP1 can be used. It is disclosed that myelination can be regulated by inhibiting the interaction of LRP1 and p75NTR and that it inhibits activation of Rho-A.

The application discloses a method for constructing a mouse severe pneumonia animal model infected by human respiratory syncytial virus and application, and relates to the technical field of viral pneumonia animal models. The method comprises the following steps: inoculating human respiratory syncytial virus on humanized IGF1R transgenic BALB / c mice, causing intra-pulmonary infection of bronchioles and / or lung tissues of the humanized IGF1R transgenic BALB / c mice, and obtaining the mouse severe pneumonia animal model infected by human respiratory syncytial virus. The method makes the mice more susceptible to human respiratory syncytial virus, and solves the problems that a conventional BALB / c mouse model cannot reproduce most of the human disease courses and generate high-titer virus proliferation, and cannot cause severe clinical symptoms due to semi-containment infection of inbred mice to human respiratory syncytial virus.

Disclosed is a genetically modified mouse having an immunoglobulin heavy chain locus engineered to insert a gene segment of a human immunoglobulin heavy chain variable region. The mouse is able to reproduce normally and produce a human-mouse chimeric antibody comprising a human heavy chain variable region and a mouse constant region. Also provided is a method for preparing the genetically modified mouse and use of the mouse.

To provide a mouse that expresses a light chain containing the human λ variable region and the mouse constant region. [Solution] A genetically modified mouse expressing a human λ variable (hVλ) sequence is provided (including mice expressing the hVλ sequence from the endogenous mouse λ light chain locus, mice expressing the hVλ sequence from the endogenous mouse κ light chain locus, and mice expressing the hVλ sequence from a transgene or episome), wherein the hVλ sequence is linked to a mouse constant sequence. A mouse is provided that serves as the source of somatically mutated human λ variable sequences useful for the production of antigen-binding proteins. A composition and method for producing an antigen-binding protein containing a human λ variable sequence containing a human antibody is also provided.

Genetically modified mice and methods for making an using them are provided, wherein the mice comprise a replacement of all or substantially all immunoglobulin heavy chain V gene segments, D gene segments, and J gene segments with at least one light chain V gene segment and at least one light chain J gene segment. Mice that make binding proteins that comprise a light chain variable domain operably linked to a heavy chain constant region are provided. Binding proteins that contain an immunoglobulin light chain variable domain, including a somatically hypermutated light chain variable domain, fused with a heavy chain constant region, are provided. Modified cells, embryos, and mice that encode sequences for making the binding proteins are provided.