Grant: Doctoral: Vanier Canada Graduate Scholarships

BACKGROUND: Heart attack and stroke together are the leading cause of death in the world. They result from atherosclerosis, a disease in which cholesterol builds up in artery walls, causing arteries to become hardened and blocked. We discovered that smooth muscle cells (SMCs), the main type of cell in the artery wall, have low levels of Lysosomal Acid Lipase (LAL), a protein that is important to process and expel excess cholesterol. We therefore believe that SMCs are resistant to releasing excess cholesterol, and that this contributes to atherosclerosis even when blood cholesterol is lowered by diet and medications. Inducing SMCs to release their excess cholesterol, then, may be a very effective new means to treat atherosclerosis. GOAL: We have shown that feeding extra LAL to SMCs in a dish increases their cholesterol export. The goal of my project is to test if inducing mouse SMCs in arteries to produce more LAL will reverse atherosclerosis, by increasing cellular release of cholesterol. APPROACH: First, I will test if inducing mouse SMCs in a dish to produce more LAL increases their ability to export cholesterol. Second, I will genetically modify mice to produce more LAL in their artery SMCs, and test if these mice develop less atherosclerosis; I will also test if increasing LAL production in SMCs can reverse atherosclerosis in mice that already have the disease. This is possible using a genetic tool that triggers LAL production specifically in SMCs. Third, I will test if increasing LAL production in the livers of mice with atherosclerosis reverses the disease. This will increase the LAL that circulates in the blood, which may also increase LAL in artery SMCs. OUTCOMES: I expect that increasing LAL production in mouse SMCs will prevent the development of atherosclerosis, and that increasing LAL in mice with atherosclerosis will reverse the disease. This would support the development of new LAL-based treatments to prevent heart attack and stroke in humans.