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The role of platelets in atherogenesis in the mouse

Institution: University of California, San Francisco
Investigator(s): Justin Hamilton, Ph.D.
Award Cycle: 2004 (Cycle 13) Grant #: 13FT-0144 Award: $34,769
Subject Area: Cardiovascular Disease
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
Atherosclerosis refers to deposits of cells, fat, and other materials in the blood vessel wall that narrow the vessel and can cause it to clot, stopping blood flow. These deposits or "plaques" are the most common cause of heart attack and some forms of stroke, and ingestion of cigarette smoke is a major risk factor for the development of these plaques. However our understanding of the initial events underlying atherosclerotic plaque development is incomplete which limits our ability to provide strategies to effectively prevent disease initiation. The overall goal of this project is to determine the role of platelets in the initiation and progression of atherosclerosis in the whole animal.

Platelets are small, blood-borne cells whose primary role is to ‘plug’ damaged blood vessels by forming blood clots, thereby preventing bleeding. Platelets may also play a role in the formation of atherosclerotic plaques. Specifically, it is thought that platelets bind to a type of white blood cell called monocytes and help these cells attach to and enter the blood vessel wall. It is well known that monocyte accumulation within the blood vessel wall is a critical cellular process for the formation of atherosclerotic plaques. Whether platelets normally contribute to atherosclerotic plaque formation is controversial. This study will use powerful and specific genetic tests to resolve this issue: we will examine the initiation and progression of atherosclerosis in mice that do not have any platelets.

Because mice do not normally display signs of atherosclerosis, platelet-deficient mice will be mated to mice genetically altered so as to be susceptible to atherosclerosis. We will then compare atherosclerotic plaque formation in atherosclerosis-prone mice that either do or do not have platelets. If platelet-deficient mice are more or less prone to atherosclerosis, we would then examine a potential mechanism for this difference by examining mice deficient in protease-activated receptor-4 (PAR4) in identical experiments. The blood-clotting enzyme thrombin is the strongest known activator of platelets and is present in atherosclerotic plaques. Because platelets from mice deficient in PAR4 do not respond to thrombin there are strong reasons to test the possibility that PAR4-deficient mice will behave like platelet-deficient mice in these studies.

We hope that the proposed studies will provide a definitive answer regarding the role of platelets in the initiation and progression of atherosclerosis. Further, if these studies turn out as we hope and we find that platelet activation is important for the initiation or progression of atherosclerosis, this information will be important in developing new strategies to prevent atherosclerosis in humans. Because of the prevalence of smoking-induced atherosclerosis, such an advance would greatly reduce the health burden produced by these patients.