Grant: Project Grant

Heart disease is a condition that affects millions of Canadians and costs the Canadian healthcare system almost 21 billion dollars annually. Atherosclerosis is the buildup of cholesterol and immune cells in the lining of the arteries (atherosclerotic plaque) and is a leading cause of heart attack and stroke. In addition to risk factors such as obesity and type 2 diabetes, the way that our body handles the build up of cholesterol in the arteries is critically important. Specialized immune cells called macrophages are able to take up and store excess cholesterol, protecting the artery wall in the process. These macrophages have specialized pathways to then transfer the cholesterol they scavenge to the circulating lipoprotein "HDL", which then carries the cholesterol to the liver, where it can be safely removed (this is why HDL-cholesterol is called the "good" cholesterol). This is known as reverse cholesterol transport. However, when this process is overwhelmed, cholesterol builds in macrophages, turning them into foam cells and causing atherosclerosis to progress. We have discovered that an important metabolic regulator called AMP-activated protein kinase (AMPK), activates reverse cholesterol transport in macrophages, but the mechanisms involved are still unknown. The objectives of this proposal are to determine how AMPK causes this beneficial removal of cholesterol from macrophage foam cells and to test if this is enough to slow or prevent atherosclerosis. We will use genetically engineered mice that are lacking the AMPK gene, as well as therapeutic compounds that specifically activate AMPK to test our hypotheses. The goal of our research is to investigate and uncover novel mechanisms that contribute to atherosclerosis and heart disease in the hopes of developing more effective prevention and therapeutic strategies.