instnjctions): Pathologic involvement of platelet activation in myocardial infarction (Ml) and ischemic stroke is well- established. Collagen is a potent platelet activator that becomes exposed to flowing blood after disruption of the endothelial surface, which occurs after vessel injury or atherosclerotic plaque rupture. Platelet-mediated thrombus formation is the proximate pathologic cause of Ml and stroke and anti-platelet therapy is a mainstay of primary and secondary cardiovascular prevention. Low dose aspirin therapy reduces the risk of Ml, stroke, and cardiovascular death by 22-25%;however, not ali individuals appear to receive equal protection from aspirin. A growing body of evidence demonstrates that aspirin-treated individuals with the highest levels of platelet reactivity in vitro are at increased risk for future cardiovascular events. Platelets express several glycoproteins on their surface that serve as collagen receptors, including glycoproteins la and lla, glycoprotein IV, and glycoprotein VI, which are potential targets for novel anti- platelet therapies. Recent studies suggest that both the expression of these glycoprotein receptors and their glycosylation contribute to binding to collagen and platelet reactivity. However, the structural bases for these glycoprotein modifications and the mechanism through which they alter platelet function have not been well characterized. The purpose of this proposal is to use emerging glycoproteomic and glycomic technologies to identify the specific alterations in platelet glycoproteins and glycans that contribute to heightened platelet reactivity and to use this information to design novel anti-thrombotic agents that target glycoproteins and complex sugars to treat cardiovascular disease with four specific aims: 1) to characterize the glycoproteins and glycans that are associated with high and low platelet reactivity in response to aspirin;2) to validate the changes in glycoproteins and glycans using complementary techniques in an independent study;3) to assess the roles of the candidate glycoproteins and glycans in collagen adhesion and platelet reactivity in vitro;and, 4) to determine the contribution of specific glycoproteins and glycans to platelet reactivity using mouse models.
Understanding how glycoprotein modifications alter platelet function will lead to a better understanding of why response to aspirin treatment varies among individuals and will allow development of novel anti- thrombotic therapies to prevent myocardial infection and stroke.
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