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

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、肺部和心血管疾病的发病率增加。吸入颗粒物（PM）引起气道高反应性、细胞炎症和粘液分泌，这些似乎在很大程度上是由活化的T细胞介导的。当T细胞被激活时，它们启动一个程序，促进生存并启动快速增殖。这种从静息状态到高度增殖状态的转换需要细胞代谢的实质性改变。目前关于T细胞代谢的教条是，静止T细胞依赖于线粒体代谢，激活T细胞依赖于糖酵解代谢，但本项目将挑战这一教条。在许多增殖细胞中，糖酵解可能是通往戊糖磷酸途径的重要通道，但它不足以提供增殖所需的全部因子。线粒体代谢需要通过TCA循环产生柠檬酸盐来制造用于膜合成的脂质。此外，已经证明线粒体ROS是促进细胞周期进程所必需的。目前的提议将利用在T细胞中有线粒体代谢基因条件缺失的小鼠来阐明线粒体代谢在T细胞激活中的作用。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。本研究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靶点。

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.