Grant: Doctoral: Vanier Canada Graduate Scholarships

Heart disease remains one of the most devastating diseases in Canada. When blood vessels become clogged with plaque buildup it becomes difficult for the heart to pump efficiently. Plaque is a complex mixture of much more than cholesterol and fat. It also contains cells from the immune system that become trapped and produce inflammation. Before these immune cells reach the plaque, they must first mature through a process called hematopoiesis. All immune cells receive characteristics from hematopoietic stem cells (HSCs) just as children receive genes passed down from their parents. Metabolism, which is the collection of biochemical reactions that convert the foods we eat into energy, occurs on many levels within our bodies. At the smallest scale, our cells manage nutrients by using tools that recognize when nutrients are low or high. These tools are proteins called AMPK (AMP-activated protein kinase) and mTORC1 (mechanistic target of rapamycin complex 1). These proteins balance each other to make sure the cell uses its nutrients in the most efficient way. Taking all of this together, we aim to understand how an unhealthy diet alters HSC metabolism and how these changes affect immune cells downstream. We ask: "does HSC metabolism affect plaque buildup?" and for therapeutic purposes, "can exercise reverse these changes at the cellular level?". To investigate this process, we will feed mice a high fat and high cholesterol diet that produces plaque. The unique mice in this study have mutations that prevent AMPK and mTORC1 from stopping each other. Using a technique that separates individual cells, we will closely examine HSCs and immune cells from mice that have been exercised or not to evaluate how metabolic signals alter plaque buildup, and whether exercise can reverse these changes in HSCs. Together, this work will highlight important considerations to be taken when treating heart disease and lay the foundation for new and exciting therapeutic strategies.