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Regulation of T Cell Responses by Chaperone-Mediated Autophagy

分子伴侣介导的自噬对 T 细胞反应的调节

基本信息

批准号：
9279041
负责人：
Fernando Macian
金额：
$ 41.75万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9279041
关键词：
Address Affect Amino Acids Antigens Autophagocytosis Biochemical CD4 Positive T Lymphocytes Cell Differentiation process Cell physiology Cells Cellular Metabolic Process Complex Data Development Ensure Enzymes Generations Goals Helper-Inducer T-Lymphocyte Homeostasis Immune response Immunization Listeriosis Lysosomes Mediating Membrane Membrane Proteins Modeling Molecular Molecular Chaperones Nutrient Organelles Pathway interactions Play Process Protein Biosynthesis Proteins Proteome Receptor Signaling Recycling Regulation Regulatory Pathway Role Signal Pathway Signal Transduction Stimulus Stress System T cell regulation T cell response T memory cell T-Cell Activation T-Cell Receptor T-Lymphocyte Translating Ubiquitin adaptive immune response extracellular in vivo in vivo Model inhibitor/antagonist limbic system-associated membrane protein lysosomal proteins mouse model multicatalytic endopeptidase complex novel novel therapeutic intervention pathogen protein degradation receptor response retinoic acid receptor alpha ubiquitin-protein ligase

项目摘要

Abstract T cell activation requires a tight regulation of positive and negative modulators of signaling pathways downstream of the T cell receptor (TCR). Degradation of specific proteins following TCR engagement is an essential regulatory mechanism that ensures efficient T cell responses. Chaperone-mediated autophagy (CMA) is an inducible form of autophagy that selectively degrades soluble cytosolic proteins that present a pentapetide targeting motif. The ability of CMA to selectively degrade proteins makes this type of autophagy a candidate to contribute to the regulation of the levels of specific signaling intermediates in response to different stimuli. We have recently shown that CMA is activated in CD4+ T cells in response to TCR engagement to regulate signaling pathways downstream of the TCR by selectively targeting inhibitors of TCR signaling for degradation in the lysosomes. In this proposal we intend to elucidate the molecular mechanisms that explain how this specific form of autophagy modulates CD4+ T cell function and characterize how CMA regulates adaptive immune responses in vivo. Our overall goal is to define CMA as a novel regulatory mechanism of T cell activation and to determine the possibility of targeting CMA to modulate T cell responses.

摘要 T细胞活化需要信号通路的正、负调节剂的严格调节在T细胞受体（TCR）下游。TCR结合后特异性蛋白质的降解是一种免疫抑制剂。重要的调节机制，确保有效的T细胞反应。分子伴侣介导的自噬是一种可诱导形式的自噬，其选择性降解呈递五肽的可溶性胞质蛋白靶向基序CMA选择性降解蛋白质的能力使这种类型的自噬成为一种候选，有助于调节响应于不同刺激的特定信号传导中间体的水平。我们最近表明，CMA在CD4+ T细胞中响应TCR接合而活化，以调节信号传导通过选择性靶向TCR信号传导的抑制剂，溶酶体在这个建议中，我们打算阐明分子机制，解释这种特定的形式，自噬调节CD4+ T细胞功能，并表征CMA如何调节适应性免疫应答 in vivo.我们的总体目标是将CMA定义为T细胞活化的一种新的调节机制，靶向CMA以调节T细胞应答的可能性。