The role of mitochondrial metabolism in T cell activation by particulate matter

线粒体代谢在颗粒物激活 T 细胞中的作用

• 批准号: 8217316
• 负责人: Laura A. Sena
• 金额: $ 4.4万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8217316
• 关键词: Address; Air Pollution; Anabolism; Animals; Antigens; Asthma; Benign; Breathing; CD28 Antigens; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cell Cycle; Cell Cycle Progression; Cell physiology; Cell surface; Cells; Citrates; Citric Acid Cycle; Clonal Expansion; Complement; Conceptions; Dendritic Cells; Disease; Disease model; Drug Delivery Systems; Exposure to; Genes; Glutamates; Glutamine; Glycolysis; Human; Hypersensitivity; Immune response; In Vitro; Incidence; Infiltration; Inflammation; Inflammatory; Knockout Mice; Lead; Left; Life Expectancy; Ligation; Lipids; Liquid substance; Lung; Lung diseases; Lymphocyte; Mediating; Membrane Lipids; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Mucous body substance; Mus; Nucleotides; Oxygen; Particulate; Particulate Matter; Pentosephosphate Pathway; Pharmacologic Substance; Process; Production; Proliferating; Rag1 Mouse; Reaction; Reactive Oxygen Species; Rest; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Source; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Wild Type Mouse; Work; aerobic glycolysis; airway hyperresponsiveness; airway inflammation; cytokine; human GPT2 protein; human subject; inhibitor/antagonist; membrane synthesis; novel; nucleotide metabolism; programs; public health relevance; response

DESCRIPTION (provided by applicant): Exposure to particulate air pollution reduces life expectancy and likely contributes to the increased incidence of asthma, allergy, and pulmonary and cardiovascular disease. Inhalation of particulate matter (PM) causes airway hyperresponsiveness, cellular inflammation, and mucus secretion, which appear to be mediated in large part by activated T cells. When T cells are activated, they initiate a program that promotes survival and initiates rapid proliferation. This switch from a resting state to a highly proliferative state requires substantial alterations in cell metabolism. The current dogma of T cell metabolism is that naive resting T cells rely on mitochondrial metabolism and activated T cells rely on glycolytic metabolism, however the current project will challenge this dogma. In many proliferating cells, glycolysis may be important as a conduit to the pentose phosphate pathway, but it is insufficient to provide the full complement of factors needed for proliferation. Mitochondrial metabolism is needed to produce citrate through the TCA cycle to make lipids for membrane synthesis. Furthermore, it has been shown that mitochondrial ROS are required to promote cell cycle progression. The current proposal will utilize mice that have mitochondrial metabolic genes conditionally deleted in T cells to elucidate the role of mitochondrial metabolism in T cell activation. We will challenge these mice with PM exposure to see if inhibition of mitochondrial metabolism could reduce T cell-mediated inflammation. The results of this study could fundamentally change the current conception of T cell metabolism, as well as provide metabolic and signaling targets that could be subject to control by pharmaceutical agents. PUBLIC HEALTH RELEVANCE: Inhalation of particulate matter (PM) induces T cell-mediated inflammation and correlates with increased incidence of asthma, allergy, and pulmonary and cardiovascular disease. This project will assess the role of mitochondrial metabolism in T cell activation and use PM exposure as a model to determine metabolic requirements of T cell-mediated inflammation. Importantly, this work will define metabolic and signaling pathways that could be modulated by pharmaceutical agents to dampen the T cell response to PM or other benign antigens.

描述（由申请人提供）：暴露于颗粒空气污染会降低预期寿命，并可能导致哮喘、过敏、肺和心血管疾病的发病率增加。吸入颗粒物（PM）会导致气道高反应性、细胞炎症和粘液分泌，这些似乎在很大程度上由活化的T细胞介导。当T细胞被激活时，它们启动一个程序，促进存活并启动快速增殖。这种从静止状态到高度增殖状态的转换需要细胞代谢的实质性改变。目前T细胞代谢的教条是幼稚的静息T细胞依赖于线粒体代谢，而活化的T细胞依赖于糖酵解代谢，然而目前的项目将挑战这一教条。在许多增殖细胞中，糖酵解作为戊糖磷酸途径的管道可能是重要的，但它不足以提供增殖所需的全部补充因子。需要线粒体代谢来通过TCA循环产生柠檬酸盐，以制造用于膜合成的脂质。此外，已经表明线粒体ROS是促进细胞周期进程所必需的。目前的提议将利用T细胞中线粒体代谢基因有条件缺失的小鼠来阐明线粒体代谢在T细胞活化中的作用。我们将用PM暴露来挑战这些小鼠，看看线粒体代谢的抑制是否可以减少T细胞介导的炎症。这项研究的结果可能从根本上改变目前对T细胞代谢的概念，并提供可受药物控制的代谢和信号传导靶点。 公共卫生关系：吸入颗粒物（PM）可诱导T细胞介导的炎症，并与哮喘、过敏、肺和心血管疾病的发病率增加相关。该项目将评估线粒体代谢在T细胞活化中的作用，并使用PM暴露作为模型来确定T细胞介导的炎症的代谢要求。重要的是，这项工作将定义代谢和信号传导途径，这些途径可以通过药物调节，以抑制T细胞对PM或其他良性抗原的反应。