Grant: Project Grant

Microglia are the immune cells residing in the brain and play key roles in its maintenance of proper functioning and defense response against infections and injuries. To date, most pathological conditions affecting the brain, ranging from neurodevelopment disorders like schizophrenia to neurodegenerative diseases like Alzheimer's disease, are accompanied by aberrant, inflammatory response that is driven by microglia. However, the mechanisms involved in coordinating microglial activity in such contexts are not well understood to this day. To large extent, the cellular functions of microglia stem from the protein that these cells express. Over the past 10 years, work by us and others has led to the identification of a number of proteins possibly involved in the regulation of gene expression in microglia in health and diseases. Among those, our preliminary results suggest that a group of proteins called myocyte enhancer factor 2 (Mef2), including Mef2a, Mef2c and Mef2d, are dominant regulators. Based on this early set of evidence, we propose here to perform a series of experiments to verify the extent to which the Mef2 protein are indeed essential to the regulation of microglial gene expression and cell functions in the brain. To do so, we will use mice in which the Mef2 proteins are specifically disabled in microglia and assess how this perturbs their activity in the healthy and diseased brain using an array of measures, including microscopy analyses and cutting-edge DNA sequencing techniques. Collectively, this research project will lead to a greater understanding of the fundamental molecular mechanisms that regulate gene expression in microglia, and by extension, of the mechanisms that underlie the cellular functions of these cells. Thus, this project is significant because it will potentially reveal novel molecular mechanisms to target with drugs to correct the aberrant activity of those cells in diseases.