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

大脑 含有神经元和称为神经胶质的非神经元细胞。它 越来越明显的是，神经胶质细胞对维持正常的 大脑和脊髓的功能。胶质细胞积极地对它们周围的环境进行采样 响应相邻细胞功能状态变化的环境， 并通过释放一系列介质来调节周围细胞的功能。非常 对用于细胞间信号转导的介质知之甚少 正常情况下神经元与神经胶质细胞之间以及神经胶质细胞之间的相互作用 生理条件。 我的NSERC资助的长期目标 研究计划旨在通过刻画小说的特征来解决这种知识鸿沟 脑内细胞间信号介质及其生理学研究 角色。 使用 从之前的探索基金中，我发现了两部小说中心 参与细胞间信号转导的神经系统(CNS)介体：线粒体转录因子A(TFAM)、 胞内蛋白，可释放到胞外 和微粒子(MPS)，它们是释放出来的小膜泡 通过中枢神经系统细胞。我们的初步数据显示，这两个中介都会影响SELECT 神经胶质细胞的功能。目标结束了 接下来的五年是研究涉及到的分子机制 TFAM和MPS对神经胶质细胞功能的调节。根据我的假设，这两个调解人参与了信号传递 在不同类型的中枢神经系统细胞之间，并且对维持脑组织至关重要 动态平衡。 具体地说，我的 小组将描述TFAM和MPS对 两种主要的胶质细胞类型，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 例如通过培养产生细胞因子和活性氧 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 动物脑内注射TFAM和MP的反应。 我们的预赛 数据显示，神经胶质细胞释放MPS的功能状态影响其 对目标细胞的影响。这可能是生理性胶质细胞间质形成的一种新机制。 信令，这将被详细研究。此外，我们还将聘用 比较蛋白质混合物中全球变化的蛋白质组学技术 由胶质细胞在Tfam和MPS刺激下分泌。 关键成果 包括(1)识别受体和 Tfam和MPS参与的细胞内信号通路；(2)确定Tfam分子中负责与 细胞受体；以及(3)发现由胶质细胞作为响应而释放的额外信号分子 给Tfam和议员们。 建议数 研究计划将显著促进对大脑的了解 用于维持中枢神经系统动态平衡的细胞间信号分子网络， 它还可以通过识别 改变或改善大脑功能的分子靶点。

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.