33 results about "LRP6" patented technology

The present invention provides reagents, compounds, compositions, and methods relating to novel interactions of the extracellular domain of LRP5, HBM (a variant of LRP5), and / or LRP6 with Dkk, including Dkk-1. The various nucleic acids, polypeptides, antibodies, assay methods, diagnostic methods, and methods of treatment of the present invention are related to and impact on Dkk, LRP5, LRP6, HBM, and Wnt signaling. Dkk, LRP5, LRP6, HBM, and Wnt are implicated in bone and lipid cellular signaling. Thus, the present invention provides reagents and methods for modulating lipid levels and / or bone mass and is useful in the treatment and diagnosis of abnormal lipid levels and bone mass disorders, such as osteoporosis.

The present invention provides reagents, compounds, compositions, and methods relating to novel interactions of the extracellular domain of LRP5, HBM (a variant of LRP5), and / or LRP6 with Dkk, including Dkk-1. The various nucleic acids, polypeptides, antibodies, assay methods, diagnostic methods, and methods of treatment of the present invention are related to and impact on Dkk, LRP5, LRP6, HBM, and Wnt signaling. Dkk, LRP5, LRP6, HBM, and Wnt are implicated in bone and lipid cellular signaling. Thus, the present invention provides reagents and methods for modulating lipid levels and / or bone mass and is useful in the treatment and diagnosis of abnormal lipid levels and bone mass disorders, such as osteoporosis.

A method for enriching a population of somatic mammary stem cells or mammary tumor stem cells based on low-density lipoprotein receptor-related protein 6 (LRP6). Also included are methods for screening for LRP6 modulators, as well as methods for reducing Wnt signaling, for treating Wnt signaling-related diseases, for detecting mammary basal-like cells, for diagnosing basal-like breast cancer, and for inhibiting proliferation of a tumor expressing LRP6, and compositions thereof.

Monoclonal antibodies against LRP6 and that block the Wnt signaling pathway are disclosed. Methods of production and use thereof are also disclosed.

The present disclosure relates to an antibody or antigen binding fragment having at least two receptor binding domains for two different binding sites of LRP6 and compositions and methods of use thereof.

The present invention relates to LRP6 constructs that bind to LRP6 receptor. The LRP6 constructs comprise at least one LRP6 binding moiety and a half-life extender molecule such that the LRP6 construct inhibit the Wnt signaling pathway without potentiation of the Wnt signal. The LRP6 constructs also have an increased half-life to provide more time for the therapeutic benefit.

The present disclosure relates to an antibody or antigen binding fragment having at least two receptor binding domains for two different binding sites of LRP6 and compositions and methods of use thereof.

The present invention relates to methods and materials used to express an HBM-like polypeptide derived from HBM, LRP5 or LRP6 in animal cells and transgenic animals. The present invention also relates to transgenic animals expressing the HBM-like polypeptides. The invention provides nucleic acids, including coding sequences, oligonucleotide primers and probes, proteins, cloning vectors, expression vectors, transformed hosts, methods of developing pharmaceutical compositions, methods of identifying molecules involved in bone development, and methods of diagnosing and treating diseases involved in bone development and lipid modulation. In preferred embodiments, the present invention is directed to methods for treating, diagnosing and preventing osteoporosis.

A novel mutant form of lrp5 and lrp6 genes, the mutant LRP5 and LRP6 receptor proteins expressed therefrom, and a cell line which expresses the mutant LRP5 and / or LRP6 receptor proteins. Methods of diagnosing, prognosing and treating LRP5 related diseases, specifically hyperthyroidism and parathyroid tumors, and kits suitable for rapid on-site testing. Finally, methods of screening for agents capable of modulating the mutant LRP5 or LRP6 receptor proteins and pharmaceutical compositions comprising the selected agents.

The invention provides a method for regulating a cellular pathway by using plant hormone ABA (Abscisic Acid) and a small molecular substance PYR (Pyrabactin). The method comprises the following steps:constructing ABA receptor proteins ABI1 and PYR1 in Arabidopsis thaliana on a human cell expression vector, then transferring into HEK293T cells respectively, adding ABA in order that the two receptor proteins undergo induced interaction, and adding a PYR inhibitor in order that the interaction degree is weakened; fusing other human cell signal pathway key proteins with the two receptor proteins,and making the two receptor proteins undergo interaction under the induction of the ABA, so that a fused signal pathway also undergoes ABA induced aggregation. According to the method provided by theinvention, a key protein LRP6 on a human Wnt pathway is selected. After fusion expression of an ABA receptor and LRP6, LRP6 aggregates under the induction of ABA, thereby promoting the production ofbeta-catenin and opening up an intracellular signal pathway. After the PYR inhibitor is added, the production amount of the beta-catenin is reduced, and the cellular pathway is closed.

The method for detecting that LRP6 is the target gene of miR-29a by using a dual-luciferase reporter gene, the purpose of the present invention is to confirm that miR-29a can be negatively expressed by targeting the 3'UTR of the LRP6 gene through a dual-luciferase reporter gene system Regulates the expression of LRP6. A method for detecting LRP6 as a target gene of miR-29a using a dual-luciferase reporter gene, the method comprising the following steps: (1) constructing a plasmid vector and performing point mutations: (2) dual fluorescence detection. The present invention The beneficial effects are as follows: provide a new method for verifying that miR-29a can negatively regulate the expression of LRP6 by targeting the 3'UTR of the LRP6 gene, and contribute to miR-29a, LRP6 and Wnt / -catenin signaling pathways Elucidation of the pathogenesis of osteogenesis-related diseases involved; contribute to the development of potential drugs for osteogenesis-related diseases involved in miR‑29a, LRP6 and Wnt / ‑catenin signaling pathways and the screening of biomarkers.

The present invention relates to the field of therapeutic methods, compositions and uses thereof, that affect, directly or indirectly, the behavior of LRP receptors. These compositions and methods result in the treatment of inflammatory, immunological and metabolic conditions. More particularly, the methods and compositions of the invention are directed to the identification of small molecules, drugs and / or pharmacological agents that affect the Wnt pathway by affecting normal complex formation among various signaling receptors, the LRP5 and LRP6 receptor, and related ligands.

The invention provides methods and compositions for modulating the Wnt signaling pathway, in particular by interfering with binding of Dkk1 or SOST with LRP5 and / or LRP6.

The loss of the SOST gene product sclerostin leads to sclerosteosis characterized byihigh bone mass (HBM). In this report, we found that sclerostin could antagonize canonical, Wnt signaling in human embryonic kidney A293 cells and mouse osteoblastic MC3T3 cells. This sclerostin-mediated antagonism could be reversed by over-expression of Wnt coreceptor LRP5. In addition, we found that sclerostin bound to LRP5 as well as LRP6 and identified the first two YWTD-EGF repeat domains of LRP5 as being responsible for the binding. Although these two repeat domains are required for transducing canonical Wnt signals, canonical Wnt did not appear to compete with sclerostin for binding to LRP5. Examination of the expression of sclerostin and Wnt7b, an autocrine canonical Wnt, during primary calvarial osteoblast differentiation revealed that sclerostin is expressed at the late stages of osteoblast differentiation coinciding with the expression of osteogenic marker osteocalcin and trailing after the expression of Wnt7b. Given the plethora of evidence indicating that canonical Wnt signaling stimulates osteogenesis, we believe that the HBM phenotype associated with the loss of sclerostin may at least in part be attributed to an increase in canonical Wnt signaling resulting from the reduction in sclerostin-mediated Wnt antagonism.

The present invention relates to compositions and methods for inducing intestinal stem cell homeogenesis and / or regeneration within intestinal tissue expressing Robo1 through administration of a Rspo1 agent and a Slit2 agent. Administration of such agents results in, for example, binding of the Rspo1 agent and Slit2 agent with Robo1, resulting in, for example, binding of the CC3 motif of Robo1 with LRP6, resulting in phosphorylation of LRP6, and ultimately, induction of intestinal stem cell homeogenesis and / or regeneration. In certain embodiments, such administration of a Rspo1 agent and a Slit2 agent is used to protect and / or prevent intestinal tissue damage resulting from exposure to an intestinal tissue damaging event (e.g., radiation). The agents and related compositions additionally find use in diagnostic and research settings.

The present invention relates to compositions and methods for inducing intestinal stem cell homeogenesis and / or regeneration within intestinal tissue expressing Robo1 through administration of a Rspo1 agent and a Slit2 agent. Administration of such agents results in, for example, binding of the Rspo1 agent and Slit2 agent with Robo1, resulting in, for example, binding of the CC3 motif of Robo1 with LRP6, resulting in phosphorylation of LRP6, and ultimately, induction of intestinal stem cell homeogenesis and / or regeneration. In certain embodiments, such administration of a Rspo1 agent and a Slit2 agent is used to protect and / or prevent intestinal tissue damage resulting from exposure to an intestinal tissue damaging event (e.g., radiation). The agents and related compositions additionally find use in diagnostic and research settings.

Provided herein are methods of screening for an agent that is a PTH agonist or antagonist. For example, provided is a method of screening for an agent that is a PTH agonist or antagonist, the method comprising contacting a cell with LRP6 and the agent to be screened, wherein the cell comprises a PTH1R, and determining the level of LRP6 binding to the PTH1R. An increased level of LRP6 binding to the PTH1R compared to a control indicates the agent is a PTH agonist. A decreased level of LRP6 binding to the PTH1R compared to a control indicates the agent is a PTH antagonist. Also provided are methods of treating a skeletal disorder in a subject, wherein the skeletal disorder is characterized by proliferative bone growth or reduced bone density.

The invention provides novel biparatopic LRP5 / LRP6 cross-reactive binding polypeptides, and more specifically novel biparatopic LRP5 / LRP6 cross-reactive immunoglobulin single variable domain constructs which can inhibit Wnt signaling pathways. The invention also relates to specific sequences of such polypeptides, methods of their production, and methods of using them, including methods of treatment of diseases such as cancer.

Provided are a modified DKK2 polypeptide according to an aspect, a nucleic acid encoding the same, a preparation method thereof, and use thereof. Accordingly, a modified DKK2 protein having an additional glycosyl group or improved binding affinity for a substrate LRP6 may be efficiently prepared, thereby being used for promoting angiogenesis or preventing or treating vascular permeability-related diseases.

The invention discloses application of a tool for repairing and maintaining a blood-brain barrier function based on targeted activation of LRP6 in preparation of a medicine for preventing and treating Alzheimer's disease, in particular to early intervention and prevention of the Alzheimer's disease. Based on the research of the invention, an optogenetics tool OptoLRP6 is utilized to target LRP6, the blood brain barrier injury can be repaired, the blood brain barrier function can be maintained, and the brain microenvironment steady state in the AD disease course can be remodeled, so that the brain endothelial cell function damage caused by A beta oligomer can be relieved, and the method can be applied to treatment and early intervention prevention of Alzheimer's disease. Therefore, development of a tool for repairing and maintaining the blood-brain barrier function based on targeted activation of the LRP6, such as an optogenetics tool, has a very good application prospect in prevention and / or treatment of the Alzheimer's disease.

The invention provides a method for regulating cell pathway by using plant hormone GA and small molecular substance PAC, and realizes the regulation switch of signal pathway in human cells. The GA receptor proteins GID1 and GAI in Arabidopsis thaliana were constructed on a human cell expression vector, and then transferred into HEK293T cells together. GA was added to induce the interaction between the two proteins. After adding the inhibitor PAC, the degree of interaction would be weakened. In this way, the key proteins in the human cell signaling pathway are fused and expressed with these two receptor proteins. The two receptor proteins interact under the induction of GA, and the fusion signaling pathway is also induced by GA. The present invention selects the key protein LRP6 on the human Wnt pathway. After the fusion expression of GA receptor and LRP6, LRP6 will aggregate under the induction of GA, thereby promoting the production of β-catenin and opening the intracellular signaling pathway. After adding PAC inhibition, the production of β-catenin is reduced and the cell pathway is closed.

Provided are a modified DKK2 polypeptide according to an aspect, a nucleic acid encoding the same, a preparation method thereof, and use thereof. Accordingly, a modified DKK2 protein having an additional glycosyl group or improved binding affinity for a substrate LRP6 may be efficiently prepared, thereby being used for promoting angiogenesis or preventing or treating vascular permeability-related diseases.

Disclosed are biomarkers, methods and assay for the identification of cancer patients who are predicted to benefit from the therapeutic administration of Wnt antagonist. The biomarkers include detection of RNF43 and ZNRF3 gene deletion, reduced RNF43 and ZNRF3 mRNA expression, reduced RNF43 and ZNRF3 protein expression, RNF43 and ZNRF3 inactivation mutation, phosphorylated LRP6, phophorylated Dishevelleds, and the expression of Frizzleds. These biomarkers can be associated with the better outcome for cancer patients treated with Wnt pathway inhibitors.