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

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*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.**