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The adaptor protein Crk in immune responses

免疫反应中的接头蛋白 Crk

基本信息

批准号：
10876527
负责人：
Dongfang Liu
金额：
$ 34.3万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-13 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10876527
关键词：
Actins Adaptor Signaling Protein Affect Apoptosis Biochemical Biological Models Birth CD8-Positive T-Lymphocytes Cell Line Cell physiology Cell-Mediated Cytolysis Cells Chronic Disease Clinical Complex Cytoskeleton Data Development DiGeorge Syndrome Disease Event Funding Future Goals Grant Host Defense Human Image Imaging Techniques Imaging technology Immune Immune response Immune system Immunity Immunologic Deficiency Syndromes Immunologics Immunotherapy In Vitro Infection Integrins Knockout Mice Knowledge Legal patent Lipid Bilayers Malignant Neoplasms Mediating Microscopy Modeling Molecular Molecular Conformation NK Cell Activation Natural Killer Cells Outcome Paper Pathway interactions Patients Peer Review Phosphorylation Phosphotransferases Play Process Proliferating Protein Family Proteins Publishing Regulation Research Resolution Role Shapes Signal Transduction Signaling Molecule Small Interfering RNA Solid Solid Neoplasm Structure System T-Lymphocyte Techniques Testing Transfection Tumor Cell Line Virus Virus Diseases Visualization Work Xenograft procedure analog cancer therapy conditional knockout congenital immunodeficiency cytotoxic cytotoxic CD8 T cells exhaust experimental study fighting immune function immunological synapse immunoregulation in vivo inhibitor kinase inhibitor molecular imaging mouse model novel novel imaging technique patient derived xenograft model population based proto-oncogene protein c-crk receptor recruit single molecule spatiotemporal superresolution microscopy tumor

项目摘要

Project Summary: This proposal is a renewal application of a previous R01 (AI130197). During the last grant period, the PI has published more than 30 peer-reviewed papers and applied for 10 patents. One of the most important discoveries directly resulting from the last funding period is that the PI has identified three promising Crk inhibitors and has filed a patent around these inhibitors (Patent #: 63/305,354). In the previous funding cycle, the PI seeks to identify the mechanism(s) by which the small adaptor protein CT10 regulator of the kinase-like (CrkL) and its phosphorylation (pCrkL) control NK cell activation and inhibition by using both human NK cells and novel NK cell-specific conditional knockout mice. The long-term goal is to use this knowledge and the novel imaging techniques to uncover the molecular basis of NK cell activation and inhibition and to develop new treatments for human primary immunodeficiency diseases and chronic diseases such as cancer and viral infection. After discovering the novel pCrkL inhibitors, we hypothesize that the newly discovered pCrkL inhibitor determines Crk’s ability to interact with critical downstream signaling molecules and ultimately shapes the actin cytoskeleton into a functional immunological synapse (IS), which can be potentially used to treat infection and cancer. Guided by strong preliminary data, in this renewal application, we will test these hypotheses via three Specific Aims: 1) Define the precise molecular mechanisms by how phosphorylation of Crk-like (pCrkL) protein inhibitors affects NK cell functions. The proposed work will bring cutting-edge imaging technology to the field of NK cell research. Experiments will determine where and when Crk is phosphorylated at the IS, as well as how it interacts with key receptors, signaling molecules, and the actin cytoskeleton with and without pCrkL inhibitors; 2) Determine the role of CrkL in T cells from patients with partial DiGeorge syndrome (pDGS). By studying one of the most common (1 in 3,000 births) immunodeficiency diseases, pDGS (mainly caused by CrkL haploinsufficiency), leveraging our previous discoveries on pDGS that demonstrate defective integrin activation in NK cells in pDGS, we will determine how the loss of CrkL affects CD8+ T cell integrin signaling and function in pDGS, which can generate novel immunotherapy (e.g., modulating integrin signaling) to treat pDGS patients in the future; 3) Discover the role of pCrkL inhibitors in cancer therapy. We identified several novel pCrkL inhibitors, which can interact with and inhibit the pCrkL protein. It inhibits the proliferation of several solid tumor cell lines in vitro, and tumor cell line-derived (CDX) xenograft and orthotopic patient-derived xenograft (PDX) mouse models; we will determine this inhibitor and its analogs’ roles in immune cell (focusing on NK and T)-mediated immune responses against solid cancers in vivo. The proposed work involves key signaling players and regulatory mechanisms and generates a novel model system to determine the role of CrkL as a master regulatory molecule. It is broadly relevant with direct clinical implications for treating primary immunodeficiency diseases and cancers.

项目总结: