Regulation of astrocyte phagocytosis and other physiological functions by molecules endogenous to the central nervous system

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The brain contains neurons and non-neuronal glia, which are critical for maintaining normal brain and spinal cord functions. Glia actively monitor their environment, respond to changes in the status of neighboring cells, and regulate functions of nearby cells by releasing various molecules. Limited information is available about the exact nature of molecules used as signals between different cell types in the central nervous system (CNS), under normal physiological conditions. The LONG-TERM OBJECTIVE of my NSERC-funded research program is to address this knowledge gap by characterizing new signaling molecules in the brain and studying their physiological roles. Recently, we have identified new CNS signaling functions of two molecules: mitochondrial transcription factor A (TFAM) and cytochrome C (CytC). These proteins are normally found inside cells, but dying or stimulated cells can release them into the extracellular space, where they can interact with glia and change their functions. The CORE GOAL of my research program for the next five years is to examine the molecular mechanisms used by TFAM and CytC to regulate physiological functions of astrocytes, the most abundant type of glia, and to discover new signaling molecules that CNS cells use to communicate with each other. I hypothesize that TFAM and CytC are intercellular signaling molecules in the CNS, which regulate astrocyte functions by interacting with specific receptors located on their surface. Specifically, my group will characterize the molecular structures responsible for the effects of TFAM on astrocytes. We will also study the effects of extracellular TFAM and CytC on select astrocyte functions, including their phagocytic activity. Phagocytosis is used to engulf cell debris and eliminate unused cellular structures; it has only recently been recognized as a key physiological function of astrocytes. In addition, we will employ proteomics techniques to compare changes in the mixture of proteins secreted by astrocytes in response to TFAM and CytC. The key expected outcomes include: 1) investigating astrocyte receptors and signaling pathways engaged by TFAM; 2) determining the part of TFAM molecule responsible for interaction with cellular receptors; 3) characterizing extracellular effects of TFAM and CytC in animal brains; 4) identifying endogenous CNS molecules that regulate astrocyte phagocytosis; and 5) discovering additional signaling molecules that are released by glia in response to TFAM and CytC stimulation. The data obtained will provide neurobiologists with new insights into the mechanisms of communication between CNS cells. The expected advancement of knowledge about the brain network of intercellular signaling molecules is critical for our understanding of regulation of diverse physiological functions and activation states of glia. The discoveries made could also lead to practical applications by identifying molecular targets for altering or improving brain function.