Determining the Impact of SREBP on Adaptive Immunity

确定 SREBP 对适应性免疫的影响

基本信息

批准号：
8447401
负责人：
STEVEN J BENSINGER
金额：
$ 36.19万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8447401
关键词：
Activated Lymphocyte Allergic Disease Antigen Receptors Antigens Atherosclerosis Autoantigens Autoimmunity Binding Proteins Biochemical CD4 Positive T Lymphocytes CD8B1 gene Cell Cycle Cell Cycle Progression Cell physiology Cells Cellular biology Cholesterol Chromatin Complex DNA biosynthesis Data Development Diabetes Mellitus Dyslipidemias Effector Cell Employee Strikes Ensure Event Foundations Frequencies Gene Expression Generations Genes Genetic Goals Growth Helper-Inducer T-Lymphocyte Hematopoietic Homeostasis Host Defense Human Immune Immune response Immune system Immunity Immunobiology Immunology In Vitro Individual Link Lipids Lymphocyte Lymphocyte Biology Lymphocyte Function Mediating Memory Metabolic Metabolic Diseases Metabolic syndrome Metabolism Mitogens Molecular Nuclear Import Obesity Pattern Play Proliferating Receptor Signaling Refractory Relative (related person)Response Elements Role Self Tolerance Signal Pathway Signal Transduction Signal Transduction Pathway Sirolimus Sterols System T cell response T memory cell T-Cell Development T-Cell Proliferation T-Lymphocyte Testing Tissues Transcriptional Regulation adaptive immunity design expectation fatty acid biosynthesis human disease immunoregulation in vivo insight interest lipid biosynthesis lipid metabolism lymphocyte proliferation neoplastic pathogen programs research study response

项目摘要

DESCRIPTION (provided by applicant): T lymphocytes are tasked with ensuring host defense against a diverse array of pathogens. They must also maintain tolerance to self-antigens to avoid autoimmunity and allergic disease. To achieve these disparate tasks, the immune system relies on a complex system of T cell proliferation, differentiation and lineage commitment. As such, understanding the fundamental mechanisms that intrinsically regulate the fate and function of an individual T cell remain important questions in immunobiology. Accumulating evidence indicates that metabolism is an important intrinsic regulator of lymphocyte function and adaptive immunity. Perturbations in the metabolic state of lymphocytes can alter T effector/helper cell function, memory T cell generation and self-tolerance. Early studies on human lymphocytes demonstrated that mitogenic signaling results in a rapid increase in de novo cholesterol and fatty acid biosynthesis. The lipid biosynthetic program precedes DNA synthesis and appears to be essential for efficient lymphocyte growth. Importantly, inhibition of the lipogenic program decreases DNA synthesis and proliferative capacity of activated lymphocytes. The molecular mechanisms underlying these striking observations have remained undefined to date. In this application, we test the hypothesis that the Sterol Response Element Binding Proteins (SREBP1 and 2), key transcriptional regulators of lipid biosynthesis and homeostasis, play a critical role in linking antigen receptor signaling with lipid metabolism, cell cycle progression and T cell fate/function. Our aims are: 1) To define the signaling pathways regulating SREBP activity and de novo lipogenesis downstream of the antigen receptor; 2) To test the hypothesis that SREBP signaling regulates cell cycle progression in activated T cells; and 3) To test the hypothesis that SREBP regulates CD8 T cell responses and immunity. The proposed studies examine a very poorly understood and potentially important aspect of lymphocyte biology. It is our expectation that these studies will increase our understanding of the crosstalk between metabolism and adaptive immunity. These studies will provide a foundation for better understanding the relationship between lipid metabolism, proliferation and differentiation in rapidly dividing hematopoietic and immune cells.

描述（由申请人提供）：T淋巴细胞的任务是确保宿主防御各种病原体。他们还必须保持对自我抗原的耐受性，以避免自身免疫性和过敏性疾病。为了实现这些不同的任务，免疫系统依赖于T细胞增殖，分化和谱系承诺的复杂系统。因此，了解本质上调节单个T细胞的命运和功能的基本机制仍然是免疫生物学中的重要问题。积累的证据表明，代谢是淋巴细胞功能和适应性免疫的重要内在调节剂。淋巴细胞代谢状态的扰动可以改变T效应器/辅助细胞功能，记忆T细胞的产生和自耐受性。对人淋巴细胞的早期研究表明，有丝分裂信号传导导致新胆固醇和脂肪酸生物合成迅速增加。脂质生物合成程序先于DNA合成，似乎对于有效的淋巴细胞生长至关重要。重要的是，抑制脂肪生成程序可降低活化淋巴细胞的DNA合成和增殖能力。迄今为止，这些引人注目的观察结果的分子机制仍然不确定。在此应用中，我们检验了以下假设：固醇响应元件结合蛋白（SREBP1和2），脂质生物合成和稳态的关键转录调节剂在将抗原受体信号与脂质代谢，细胞周期进展和T细胞及时效果联系起来方面起着至关重要的作用/功能。我们的目的是：1）定义调节抗原受体下游SREBP活性和从头脂肪形成的信号通路； 2）测试SREBP信号传导调节活化T细胞中细胞周期进程的假设； 3）测试SREBP调节CD8 T细胞反应和免疫力的假设。拟议的研究研究了淋巴细胞生物学的一个非常了解且潜在的重要方面。我们期望这些研究将增加我们对代谢和适应性免疫之间串扰的理解。这些研究将为更好地理解脂质代谢，增殖和迅速分裂的造血和免疫细胞的分化之间的关系提供基础。