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Role of CD3delta in T-lymphocyte function

CD3delta 在 T 淋巴细胞功能中的作用

基本信息

批准号：
8122174
负责人：
BATU ERMAN
金额：
$ 5.03万
依托单位：
SABANCI UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8122174
关键词：
Antibodies Antigen-Presenting Cells Binding Biochemical Biochemistry Biological Biological Assay Biological Models CD36 gene Cell Line Cells Clinical Complement Complementary DNA Complex Cytoplasmic Tail Defect Development Docking EMSA Event Experimental Models Fluorescence Resonance Energy Transfer Generations Goals High-Risk Cancer Human Immune system Immunity Immunocompromised Host Immunologic Deficiency Syndromes In Vitro Incidence Individual Knockout Mice Knowledge Laboratories Lead Ligands Link Lymphocyte Function Malignant Neoplasms Mature T-Lymphocyte Membrane Modeling Molecular Mus Patients Peptide/MHC Complex Play Proteins Receptor Signaling Recruitment Activity Reporter Genes Role Signal Transduction Site Staging Stimulus Surface System Systems Development T-Cell Receptor T-Lymphocyte Testing Transgenes Transgenic Mice Transgenic Organisms Variant Yeasts crosslink fight against genetically modified cells immune activation in vivo mutant programs receptor receptor expression research study thymocyte tissue culture tumor

项目摘要

DESCRIPTION (provided by applicant): T-lymphocyte deficient mice and immunocompromised humans have significantly higher incidence of various cancers, indicating that T lymphocytes play a critical role in tumor surveillance and rejection. Understanding how T cells develop and respond to T cell receptor (TCR) signals in a murine experimental model system will enhance our understanding of how T cells in immuno-competent humans perform surveillance against tumors. The TCR is a transmembrane receptor which has multiple signaling subunits. There is a gap in knowledge about the unique functions of individual signaling subunits of the TCR. The primary objective of his proposal is to understand how T lymphocytes respond to external stimuli when a key component of their TCR is absent. We have focused on the role of the CD3delta subunit in TCR signal transduction. CDSdelta deficiency has been observed in humans and results in an immunodeficiency syndrome. Unlike the other TCR subunits, CDSdelta is unique, in that not all TCR signaling events require this subunit. Our preliminary studies indicate that CD3delta deficient TCR signals are insufficient for the generation mature T cells in vivo, even though these receptors can signal if stimulated in vitro. This finding led to our central hypothesis that CDSdelta is responsible for the TCR to interact with CD4 or CDS co-receptors so that it can recognize MHC:peptide ligands on antigen presenting cells. We propose to use CDSdelta deficient cell lines grown in our tissue culture laboratory and murine models supplemented by CDSdelta transgenes to identify the molecular mechanism of this protein's contribution to TCR signal transduction. We will perform molecular biological and biochemical experiments that will lead to the cause of the defect observed during immune system development in the absence of CDSdelta. The objective of this proposal is to 1) attempt to overcome this developmental defect, 2) determine the mechanism of CDSdelta deficient TCR signals, 3) determine if CDSdelta interacts with co-receptor molecules on the surface of T lymphocytes. The genetically modified cell lines and mice created in this proposal will enable us to explore the function of ligand dependent and ligand independent signaling in T lymphocytes. A better understanding of CDSdelta deficient TCR signals will allow us to overcome the immunodeficiencies (and associated higher cancer risk) in patients that lack this protein.

描述（申请人提供）：T淋巴细胞缺陷小鼠和免疫功能低下的人类各种癌症的发病率显着较高，表明T淋巴细胞在肿瘤监测和排斥中发挥着关键作用。了解 T 细胞如何在小鼠实验模型系统中发育并响应 T 细胞受体 (TCR) 信号，将增强我们对具有免疫能力的人类中的 T 细胞如何对肿瘤进行监视的理解。 TCR是一种跨膜受体，具有多个信号亚基。关于 TCR 各个信号亚基的独特功能的认识存在差距。他的提议的主要目的是了解当 T 淋巴细胞的 TCR 关键成分缺失时，T 淋巴细胞如何响应外部刺激。我们重点关注 CD3delta 亚基在 TCR 信号转导中的作用。已在人类中观察到 CDSdelta 缺陷并导致免疫缺陷综合征。与其他 TCR 亚基不同，CDSdelta 是独特的，因为并非所有 TCR 信号传导事件都需要该亚基。我们的初步研究表明，CD3delta 缺陷的 TCR 信号不足以在体内生成成熟 T 细胞，即使这些受体在体外受到刺激时可以发出信号。这一发现引出了我们的中心假设，即 CDSdelta 负责 TCR 与 CD4 或 CDS 共受体相互作用，从而使其能够识别抗原呈递细胞上的 MHC：肽配体。我们建议使用在我们的组织培养实验室中生长的 CDSdelta 缺陷细胞系和补充有 CDSdelta 转基因的小鼠模型来确定该蛋白质对 TCR 信号转导的分子机制。我们将进行分子生物学和生化实验，以找出在缺乏 CDSdelta 的情况下免疫系统发育过程中观察到的缺陷的原因。该提案的目的是 1) 尝试克服这种发育缺陷，2) 确定 CDSdelta 缺陷 TCR 信号的机制，3) 确定 CDSdelta 是否与 T 淋巴细胞表面的共受体分子相互作用。本提案中创建的转基因细胞系和小鼠将使我们能够探索 T 淋巴细胞中配体依赖性和配体非依赖性信号传导的功能。更好地了解 CDSdelta 缺陷 TCR 信号将使我们能够克服缺乏这种蛋白质的患者的免疫缺陷（以及相关的较高癌症风险）。