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

细胞外释放的线粒体转录因子 A 和微粒对脑胶质细胞功能的调节

• 批准号: RGPIN-2015-06321
• 负责人: Klegeris, Andis
• 金额: $ 2.04万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=614079
• 关键词: Regulation; brain; glial; cell; functions

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 cells. This may be a novel mechanism of physiological interglial signaling, which will be studied in detail. In addition, we will employ proteomics techniques to compare global changes in the mixture of proteins secreted by glial cells in response to stimulation by Tfam and MPs. The key outcomes include (1) identifying the receptors and intracellular signaling pathways engaged by Tfam and MPs; (2) determining the part of the Tfam molecule responsible for interacting with the cellular receptors; and (3) discovering additional signaling molecules that are released by glia in response to Tfam and MPs. The proposed research program will significantly advance the knowledge about the brain network of intercellular signaling molecules used to maintain CNS homeostasis, which could also lead to practical applications through the identification of molecular targets for altering or improving brain function.

大脑 包含神经元和非神经元的神经胶质细胞。它 越来越明显的是，胶质细胞对于维持正常的 大脑和脊髓的功能。胶质细胞积极地对周围环境进行采样 环境响应于邻近细胞的功能状态的变化， 并通过释放一系列介质来调节周围细胞的功能。非常 对于细胞间信号传导的介质知之甚少 神经元和神经胶质之间以及正常情况下神经胶质细胞之间 生理条件。 我的NSERC资助的长期目标 研究计划是通过描述新的 脑内细胞间信号传导介质及其生理功能的研究 角色 与 从以前的发现补助金的资金，我已经确定了两个新的中心 参与细胞间信号传导的神经系统（CNS）介质：线粒体转录因子A（Tfam）， 细胞内的蛋白质，可以释放到细胞外 空间;和微粒（MP），这是小的膜囊泡， CNS细胞。我们的初步数据表明，这两种介质影响选择， 神经胶质细胞功能目标结束 未来五年的任务是研究 通过Tfam和MP调节神经胶质功能。我的假设是，这两种介质参与了信号传导， 在不同的中枢神经系统细胞类型之间， 体内平衡 具体来说，我 小组将描述Tfam和MP对 两种主要的神经胶质细胞类型，星形胶质细胞和小胶质细胞。我们将测量不同的神经胶质反应 例如通过使用培养的细胞产生细胞因子和活性氧物质 脑源性神经胶质细胞和模型细胞系。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 数据显示，神经胶质细胞释放MP的功能状态影响其 对靶细胞的影响。这可能是一种新的神经胶质细胞间的生理性分化机制。 信号，这将被详细研究。此外，我们将聘请 蛋白质组学技术比较蛋白质混合物的全球变化 由神经胶质细胞响应于Tfam和MP的刺激而分泌。 的主要成果 包括（1）识别受体， Tfam和MP参与的细胞内信号传导途径;（2）确定Tfam分子负责与MPs相互作用的部分。 细胞受体;（3）发现神经胶质细胞在反应中释放的其他信号分子 Tfam和国会议员。 拟议 一项研究计划将大大推进对大脑的认识 用于维持CNS稳态的细胞间信号分子网络， 这也可能导致实际应用， 改变或改善大脑功能的分子靶点。