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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：
9428868
负责人：
Dongfang Liu
金额：
$ 53.15万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-09 至 2018-02-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9428868
关键词：
Actins Adaptor Signaling Protein Affect Algorithms Apoptosis Autologous Automobile Driving Biochemical Biological Models Biological Response Modifiers Birth CRKL protein Cell Line Cell physiology Cell-Mediated Cytolysis Cells Chronic Disease Clinical Complex Custom Cytoplasmic Granules Cytoskeleton Data DiGeorge Syndrome Disease Effector Cell Energy Transfer Event Explosion Fluorescence Glioblastoma Goals Hematologic Neoplasms Host Defense Human Image Imaging Techniques Imaging technology Immune Immune response Immune system Immunity Immunologic Deficiency Syndromes Immunologics Immunology Immunoprecipitation In Vitro Infection Killer Cells Knockout Mice Knowledge Lipid Bilayers Lytic Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Microscopy Modeling Molecular Molecular Conformation NK Cell Activation Natural Killer Cells Patients Phosphorylation Phosphotransferases Play Protein Family Proteins Recruitment Activity Regulation Research Resolution Role Shapes Signal Transduction Signaling Molecule Small Interfering RNA Stem cells Structure Synapses System Techniques Testing Tissues Transfection Viral Cancer Virus Virus Diseases Work biological systems cell killing cell mediated immune response congenital immunodeficiency cytotoxic experimental study fighting gene therapy immunological synapse immunoregulation in vivo insight kinase inhibitor knock-down live cell microscopy malignant breast neoplasm molecular imaging novel novel therapeutics population based protein function proto-oncogene protein c-crk receptor sarcoma single molecule spatiotemporal

项目摘要

Project Summary Natural killer (NK) cells play an important role in the human immune response to infection and malignancy. How these cells effectively distinguish between diseased and healthy tissue is one of the key unsolved problems in immunology today. The proposed work seeks to identify the mechanism(s) by which the small adaptor protein CT10 regulator of kinase (Crk), and its phosphorylation, 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 developed herein 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. NK cells kill target cells through the polarized release of lytic granules through a specialized region of cell-cell contact known as the immunological synapse (IS). Through previous studies of the cytotoxic (Liu, D. et al., Immunity, 2009, Cover Article) and inhibitory (Liu, D. et al., Immunity, 2012) IS, we discovered that Crk plays an essential upstream role at the IS, influencing signaling events required for both activation and inhibition. The molecular mechanisms underlying this dual role, however, remain unclear. We hypothesize that receptor-driven phosphorylation of Crk acts as a molecular switch, driving a conformational change, which in turn determines Crk's ability to interact with critical downstream signaling molecules and ultimately shapes the actin cytoskeleton into a functional IS. Guided by strong preliminary data, we will test these hypotheses via three Specific Aims: 1) Define the precise molecular mechanisms by which Crk controls NK cell activation and inhibition. The proposed work capitalizes on the recent explosion in single molecule imaging and will bring cutting-edge single molecule imaging technology to the field of NK research, with a focus on human primary immunodeficiency diseases; 2) Determine the role of Crk-like protein (CrkL) in NK cells from patients with partial DiGeorge syndrome (pDGS). Using one of most common (1 in 4,000 births) immunodeficiency diseases, pDGS (mainly caused by CrkL haploinsufficiency), we will determine how loss of CrkL function affects NK cell-mediated cytotoxicity in pDGS and its molecular mechanisms; 3) Determine whether Crk is required for NK function in vivo. Leveraging novel NK cell-specific Crk knockout mice that we have already generated, we will determine the roles that Crk molecules play in NK cell-mediated immune responses to viral infection and cancer in vivo. The proposed work involves key signaling players and novel regulatory mechanisms and is broadly relevant with direct clinical implications for the treatment of primary immunodeficiency diseases and cancer because elevated expression and increased phosphorylation of Crk are common to various cancers (e.g., lung cancer, breast cancer, glioblastoma, sarcomas, ovarian cancer, and hematopoietic cancers). The proposed work also generates a novel model system in which to determine Crk's role as a master regulatory molecule. !

项目总结