Grant: Team Grant: Chronic Disease Risk and Intervention Strategies - LOI

Cholesterol circulates in blood and is essential for the integrity of cells and for the production of steroid hormones and vitamin D. About 75 percent of cholesterol circulating in the bloodstream is made in the liver. Hypercholesterolemia corresponds to an accumulation of cholesterol in the blood (superior to 240 milligrams per deciliter) and increases the risk of heart disease. Indeed, cholesterol accumulates on vessel walls to form plaques. When these deposits become too large, they block blood vessels and decrease the flow of blood. If this happens in the arteries supplying the heart, a heart attack will occur. This disease called atherosclerosis is the major cause of death from heart disease. Primary treatments involve dietary changes and exercise. If this lifestyle change is not sufficient, then patients are prescribed statins, drugs that diminish liver cholesterol production. However, this therapy is efficient in 60% of the cases only, and many patients on statin therapy complain of secondary effects, like muscular pains. Accordingly, alternative cholesterol-lowering drugs are needed. In 2003, a new gene encoding the protein PCSK9 was discovered by the team leader of our present program. Rare mutations in the PCSK9 gene are responsible for familial hypercholesterolemia. PCSK9 increases the levels of circulating cholesterol. Intelligent drugs that target PCSK9 will definitely reduce the incidence of heart disease. Our goal is to fully understand the fundamental biology of PCSK9 and its underlying mechanism of action in cholesterol control, and to translate this knowledge into novel, more effective therapies to be tested in the clinic.