Grant: Doctoral Research Award: Canada Graduate Scholarships

Heart attacks and stroke are two of the leading causes of death in Canada every year. Both are affected by high levels of "bad cholesterol" in the blood, known as LDL-cholesterol. Through a process called atherosclerosis, excess LDL-cholesterol builds up in blood vessels, forming plaques that reduce blood flow to the heart or brain. White blood cells of the immune system enter these plaques and release a protein called MMP12 that destabilizes the plaque and could cause it to rupture, which in turn could result in heart attack or stroke. Therefore, reducing the amount of LDL-cholesterol is important to reduce the risk of heart attacks and stroke amongst Canadians. Newly developed drugs to reduce LDL-cholesterol in the blood work by blocking a protein called PCSK9, which normally increases LDL-cholesterol in the blood by preventing the liver from clearing it. These drugs are effective, but are expensive and difficult to produce on a large scale, and must be injected into the skin rather than simply swallowed as a pill. Therefore, more research is needed to understand how to develop better drugs to block PCSK9 or other proteins such as MMP12, which might be important for the effects of PCSK9 on LDL-cholesterol levels. We have discovered that PCSK9 can be cut and modified by MMP12 from white blood cells, and by a close relative called MMP14 that is produced by the same white blood cells and by cells in the liver that are important regulators of LDL-cholesterol levels. My PhD research focuses on understanding how PCSK9 is modified by MMP12 and MMP14, and on discovering the effects of these modifications on LDL-cholesterol levels and atherosclerosis. This research could contribute to developing the next generation of drugs that would help millions of Canadians with high LDL-cholesterol levels who are at risk of atherosclerosis, heart attacks and stroke.