Grant: Operating Grant-PA: INMD Start Up Funds (bridge funding) - New Investigators

Cholesterol is a normal component of cells and is essential to the proper function of the human body. However, several factors such as heredity, obesity or an unhealthy diet can increase blood cholesterol levels, a major risk factor for heart diseases. The majority of heart attacks and strokes are caused by atherosclerosis, the process by which arteries become clogged by fatty deposits called plaque. The higher is the level of a certain form of cholesterol called "bad" cholesterol, the faster atherosclerosis develops. The present work explores the roles of a protein called PCSK9 that is a major cause of elevated blood cholesterol. This protein acts as a brake on the entry of "bad" cholesterol into liver cells so that blood cholesterol levels increase dramatically. Therefore, removing this brake represents a very promising therapy to lower the level of "bad" cholesterol and the risk of premature atherosclerosis. However, it is not well understood how PCSK9 blocks the removal of circulating cholesterol. Previous observations and recent studies in my laboratory indicate that specific proteins can control the harmful activity of PCSK9. The main objective of our research project is to characterize how these newly identified proteins modify the function of PCSK9. Using a combination of biochemical approaches together with relevant cell and animal models, our studies will help to elucidate the mechanism of PCSK9 and to develop inhibitors for the prevention of cardiovascular diseases.