Regulation of brain glial cell functions by extracellularly released mitochondrial transcription factor A and microparticles

大脑包含神经元和非神经元细胞，称为神经胶质。越来越明显的是，神经胶质对于维持大脑和脊髓的正常功能至关重要。神经胶质细胞对周围环境进行主动采样，以响应邻近细胞功能状态的变化，并通过释放一系列介质来调节周围细胞的功能。在正常生理条件下，神经元和神经胶质细胞之间以及神经胶质细胞之间用于细胞间信号传导的介质知之甚少。我的NSERC资助的研究项目的长期目标是通过描述大脑中新的细胞间信号介质并研究它们的生理作用来解决这一知识缺口。在以前的发现基金的资助下，我已经确定了两种新的中枢神经系统（CNS）介导剂参与细胞间信号传导：线粒体转录因子A（Tfam），一种细胞内蛋白质，可以释放到细胞外空间;和微粒（MP），这是由CNS细胞释放的小膜囊泡。我们的初步数据表明，这两种介质影响选择 * 神经胶质细胞的功能。未来五年的目标是研究Tfam和MPs调节神经胶质功能所涉及的分子机制。我的假设是，这两种介质参与不同CNS细胞类型之间的信号传递，并且对维持脑组织的稳态至关重要。 * 具体来说，我的 * 小组将描述Tfam和MP对 * 两种主要神经胶质细胞类型（星形胶质细胞和小胶质细胞）的影响。我们将使用培养的 * 脑源性胶质细胞和模型细胞系来测量不同的胶质反应 *，例如细胞因子和活性氧的产生。我们还将研究神经胶质细胞对Tfam和MP注射到动物脑中的反应。我们的初步数据表明，胶质细胞释放MP的功能状态影响其对靶细胞的作用

*The brain*contains neurons and non-neuronal cells called glia. It*is increasingly evident that glia are critical for maintaining the normal*functioning of the brain and spinal cord. Glia actively sample their surrounding*environment responding to changes in the functional status of neighbouring cells,*and regulate functions of surrounding cells by releasing a range of mediators. Very*little is known about the mediators that are used for intercellular signaling*between neurons and glia as well as between glial cells themselves under normal*physiological conditions.***The LONG-TERM OBJECTIVE of my NSERC-funded*research program is to address this knowledge gap by characterizing novel*intercellular signaling mediators in the brain and studying their physiological*roles.****With*funding from a previous Discovery Grant, I have identified two novel central*nervous system (CNS) mediators involved in intercellular signaling: mitochondrial transcription factor A (Tfam), an*intracellular protein, which could be released into the extracellular*space; and microparticles (MPs), which are small membrane vesicles that are released*by CNS cells. Our preliminary data show that both these mediators affect select*glial cell functions. The GOAL over*the next five years is to examine the molecular mechanisms involved in*regulation of glial functions by Tfam and MPs. It is my hypothesis that these two mediators participate in the signaling*between different CNS cell types, and are critical for maintaining brain tissue*homeostasis.  ****Specifically, my*group will characterize the effects of Tfam and MPs on*the two main glial cell types, astrocytes and microglia. We will measure different glial responses*such as production of cytokines and reactive oxygen species by using cultured*brain-derived glial cells and model cell lines. We will also study glial cell*responses to Tfam and MP injections into animal brain.****Our preliminary*data show that the functional state of glial cells releasing MPs influences their*effects on target cell