Grant: CIHR Fellowship

Microglia, resident brain immune cells, are crucial in maintaining brain equilibrium throughout the lifespan. Their functions include surveying their environment to eat and destroy pathogens (by phagocytosis). Microglia are key players in the pathogenesis of glioblastoma (GBM), a highly aggressive brain tumor characterized by a dismal prognostic, particularly for male patients. Men's poor survival rates are associated with an increase in glycolytic metabolism, a shift that causes structural and cellular damage over time. Efforts to prolong the life of patients are impeded by the resistance of GBM to traditional treatments, highlighting the necessity to uncover novel interventions. Despite research investigating microglia in GBM, the effect of sex on microglial function and metabolism in GBM has not been elucidated yet, which is important to understand if sex-specific microglial differences contribute to the differences in the pathogenesis across sexes. To this end, this study aims to determine how GBM affects microglial metabolism, functions and protein expression across sexes. As metabolism and function are highly intertwined, we will rescue microglial alterations by reprogramming their metabolism. This research will utilize ex vivo state-of-the-art techniques to correlate the protein signature of microglia to the structure of their cellular content, combined with in vitro assessment of the metabolic and phagocytic characteristics of microglia. The data obtained will help demystify the sex-specific differences observed, notably metabolic variances, a feature particularly affected by GBM. This study has a high-translational aspect as metabolic approaches have previously been used to treat certain cancers, notably through diet (e.g., ketogenic diet) or are currently in clinical trials (e.g., metformin). Therefore, the novel knowledge obtained through this study could be essential to target microglia for eventual therapeutic avenues.