Signal-dependent regulators of LXR activity for the treatment of atherosclerosis

Cardiovascular disease is the leading cause of death in the Western world and therefore represents a significant health care concern and a major burden on resources for Canadians. For atherosclerosis, plaque formation in arterial walls occurs as an inflammatory response to high cholesterol, with mature plaques at significant risk for rupture, which not only releases destructive inflammatory mediators into the circulatory system, but can also occlude major arteries resulting in heart attack or stroke. Prior attempts to treat atherosclerosis by preventing cholesterol accumulation in these immune cells, namely macrophages, have produced potentially lethal side effects due to the nature of the protein specifically targeted by these drugs. However, by defining additional regulatory mechanisms responsible for preventing cholesterol accumulation, new therapeutic targets could be identified. We therefore propose to identify and characterize the molecular regulatory mechanisms controlling cholesterol removal from macrophages. This will provide important insights into the pathways involved in cholesterol regulation and lesion development, and will allow for the design of therapeutics for the treatment and prevention of atherosclerosis in humans.