Grant: Discovery Grants Program - Individual

MicroRNAs (miRNAs) are small, highly conserved non-coding RNA molecules that are involved in endogenous mRNA silencing and post-transcriptional regulation of gene expression. In the central nervous system (CNS), each major cell type has a distinct miRNA signature (termed miRNAome). As a consequence, the differential expression of miRNAs contributes to the unique expression of proteins, thereby influencing overall phenotype and function. Upon disruption of homeostasis, expression profiles of miRNAs are rapidly altered, leading to changes in the expression of proteins within a particular cell. Therefore, miRNAs play critical roles in fundamental cellular processes, and both directly and indirectly influence the complex CNS environment. Homeostatic communication between neurons and the various forms of glia helps maintain a healthy functioning nervous system. This communication is complex and can be mediated by either direct physical interactions or via different molecules and/or soluble factors that are released from cells. In recent years, extracellular vesicles (EVs) have emerged as key players involved in cell-cell communication, including within cells of the CNS. EVs are small lipid bilayer particles that are released from most cells and contain molecular cargo (including miRNAs) that can be shuttled between neighbouring cells and play an important role in intercellular communication. In recent years, my laboratory has developed the necessary expertise to purify, quantify, and phenotype EVs, while also assessing how miRNAs are shuttled via EVs between cells of the CNS. This novel work will not only help to further understand the roles of specific miRNAs, but also how cells of the CNS communicate with one another. Finally, using a variety of technical approaches, the objectives outlined within this application will provide HQP with a unique training environment to acquire new skills and help advance the field of basic neuroscience. In this application, our long-term objective is to better understand how specific miRNA molecules can impact the overall fate and function of CNS cells. To reach this long-term goal, we will focus on the following short-term objectives: 1) investigate how altering specific miRNA expression within microglia and astrocytes can directly impact cellular function, 2) Assess how altered miRNA expression within microglia specifically directly influences the biology of other CNS-resident cells, including oligodendrocyte progenitor cells (OPCs), astrocytes, and neurons, and 3) Assess the ability of microglia- and astrocyte-derived EVs to package specific miRNA molecules of interest and investigate their impacts on recipient cells. Taken together, achieving these specific objectives will support HQP training, elucidate the role of miRNAs as regulators of glial and neuronal cell function, and provide novel insights into EV-mediated transfer of miRNAs as a fundamental aspect of intercellular communication within the CNS.