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T Cell Receptor Signaling by Phosphorylated Forms of TCR

TCR 磷酸化形式的 T 细胞受体信号传导

基本信息

批准号：
7253119
负责人：
NICOLAI Stanislas Cyrille VAN OERS
金额：
$ 29.58万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-03-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7253119
关键词：
3-Dimensional Accounting Amino Acid Sequence Autoimmune Diseases Autoimmune Process Bacterial Infections Binding Biochemical Biological Assay CD3 Antigens CDKN1A gene Cell Survival Cell membrane Cell physiology Complex Development Engineering Failure Family Image Immune Immune response Immune system Immunity Infection Lead Life Ligand Binding Ligands Listeria Lymphocyte Lymphocyte Function Membrane Microdomains Minor Molecular Monitor Motion Mus Mutation P23 Peripheral Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Population Process Property Protein Tyrosine Kinase Protein Tyrosine Phosphatase Protein-Serine-Threonine Kinases Proteins Receptor Signaling Research Personnel Role Series Signal Transduction Signaling Protein T-Cell Development T-Cell Receptor T-Lymphocyte Techniques Therapeutic Transgenic Mice Transgenic Organisms Translating Tumor Suppression Tyrosine Tyrosine Phosphorylation Site Viral Virus Diseases base immune function immunological synapse insight molecular mass oncoprotein p21 pathogen programs receptor receptor function response selective expression synaptogenesis transmission process

项目摘要

DESCRIPTION (provided by applicant): T cells are an essential component of the immune system, recognizing the presence of foreign pathogens and setting in motion very specific intracellular responses to protect the body from serious infection. The T cell receptor (TCR) complex controls these T cell processes. It discriminates very subtle differences in the foreign molecules that it binds to, responding by activating the appropriate intracellular signals that will lead to an effective immune response. The underlying objective of this application is to understand exactly how the T cell receptor controls T cell development and immune functions. This is critical because failure to activate an appropriate response leads to serious infections and inappropriate activation leads to autoimmune diseases. This proposal focuses on the role of the TCRzeta subunit, and the deceptively simple phosphorylation of specific tyrosine residues that is at the core of the TCR's ability to regulate T cell development and immune functions. The TCRzeta subunit forms two discrete tyrosine phosphorylated forms of 21 and 23 kDa (p21 and p23). Preliminary results using a series of transgenic mice that differentially express these phosphorylated proteins indicate that p21 and p23 possess essential non-redundant functions in controlling T cell development, survival, and functions during infections. There are four specific aims in this proposal. The first is to identify the molecular mechanism(s) responsible for the different functions of p21 and p23. The second involves delineating the contribution of p21 to T cell survival. In the third, the functional contribution of phosphorylated zeta to T cells during immune responses to bacterial infections will be determined. The forth aim involves a characterization of phosphatases and kinases that regulate TCR functions. The approaches will incorporate sophisticated biochemical and 3-d imaging studies with the various TCRzeta transgenic lines. The studies will include immunological assays to monitor lymphocyte functions during normal lymphocyte development as well as during infections and autoimmune scenarios.

描述（由申请人提供）：T细胞是免疫系统的重要组成部分，识别外来病原体的存在，并启动非常特定的细胞内反应，以保护身体免受严重感染。T细胞受体（TCR）复合物控制着这些T细胞过程。它能分辨出与之结合的外来分子的细微差别，通过激活适当的细胞内信号来做出反应，从而导致有效的免疫反应。这项应用的潜在目标是了解T细胞受体是如何控制T细胞发育和免疫功能的。这是至关重要的，因为未能激活适当的反应会导致严重感染，而不适当的激活会导致自身免疫性疾病。这一建议的重点是TCRzeta亚基的作用，以及TCR调节T细胞发育和免疫功能的能力的核心——特定酪氨酸残基的看似简单的磷酸化。TCRzeta亚基形成21 kDa和23 kDa两种独立的酪氨酸磷酸化形式（p21和p23）。通过一系列表达这些磷酸化蛋白的转基因小鼠的初步结果表明，p21和p23在控制T细胞的发育、存活和感染期间的功能方面具有必要的非冗余功能。这项建议有四个具体目标。首先是确定导致p21和p23不同功能的分子机制。第二项涉及描述p21对T细胞存活的贡献。第三，将确定磷酸化zeta对T细胞在对细菌感染的免疫反应中的功能贡献。第四个目标涉及调节TCR功能的磷酸酶和激酶的表征。这些方法将结合复杂的生化和三维成像研究与各种TCRzeta转基因系。这些研究将包括在正常淋巴细胞发育以及感染和自身免疫情况下监测淋巴细胞功能的免疫学分析。