Grant: Project Grant

Healthier nutrition and lifestyle, along with cholesterol-lowering drugs (statins) have lowered the rates of heart disease in Canada, yet it is still a major health concern and the second leading cause of death. Our research is focused on understanding how the metabolism of cells important for CVD might be controlling its onset. The job of a protein called HMG-CoA reductase (HMGCR for short, which is the protein that is shut down by statin drugs) is to make cholesterol, but also something called isoprenoid groups, which are small attachments that are added to proteins to help or control how they work. Since HMGCR is such an important protein, it has many layers of control. One of these layers of control is called phosphorylation (which acts very quickly) and we know that a master regulator of cell metabolism (a protein called AMPK) can switch off HMGCR using this type of control. What we don't fully understand is the importance of this control step in cholesterol and isoprenoid production. We have genetically engineered mice so that they have a very specific and small mutation that makes their HMGCR completely resistant to the control that AMPK would usually have. Using these mice, we saw that when the HMGCR protein (cholesterol and isoprenoid production) was not controlled by AMPK, atherosclerosis (what leads to heart disease) is much worse. The current proposal is focused on understanding HOW and WHY this happens. We will build on our early results and experiments to see if having more heart disease is because of something to do with cholesterol or the use of isoprenoids, and also whether this metabolic pathway is important for making the cells that, in the end, form the plaque found in heart disease. It is our hope that by understanding how this pathway controls the early stages of heart disease, and how this might be different in males and females, we can potentially fine-tune or make new drugs that will further help Canadians affected by this disease.