Roles of Platelet Glycoproteins and Glycans on Platelet Reactivity and Cardiovasc

实例)： 心肌梗死和缺血性卒中中血小板活化的病理参与是很好的 已经成立了。胶原蛋白是一种有效的血小板激活剂，在血液流动中断后会暴露在血液中 血管损伤或动脉粥样硬化斑块破裂后的内皮表面。血小板介导的 血栓形成是ML和卒中的直接病理原因，抗血小板治疗是一种 一级和二级心血管预防的中流砥柱。小剂量阿司匹林治疗可降低 急性髓细胞白血病、中风和心血管疾病的死亡率降低22-25%；然而，ALI患者似乎没有得到同样的好处 保护身体免受阿司匹林的伤害。越来越多的证据表明，服用阿司匹林的患者 体外最高水平的血小板反应性增加了未来心血管事件的风险。 血小板表面表达几种作为胶原受体的糖蛋白，包括 糖蛋白1a和11a、糖蛋白IV和糖蛋白VI是新型抗肿瘤药物的潜在靶点 血小板疗法。最近的研究表明，这些糖蛋白受体的表达和它们的 糖基化有助于与胶原结合和血小板的反应性。然而，这些的结构性基础 糖蛋白修饰及其改变血小板功能的机制一直不是很好。 特色化的。 这项建议的目的是使用新兴的糖蛋白质组和糖组学技术来识别 血小板糖蛋白和多糖的特异性改变，有助于提高血小板的反应性和 利用这些信息设计针对糖蛋白和复合糖的新型抗血栓药物 治疗心血管疾病有四个特定目标：1)表征糖蛋白和糖链 与对阿司匹林反应的高和低血小板反应有关；2)验证 在一项独立研究中使用互补技术的糖蛋白和葡聚糖；3)评估其作用 候选糖蛋白和多糖在体外对胶原黏附和血小板反应性的影响；以及，4) 利用小鼠模型确定特定糖蛋白和多糖对血小板反应性的贡献。 相关性(请参阅说明)： 了解糖蛋白修饰如何改变血小板功能将有助于更好地理解 为什么对阿司匹林治疗的反应因人而异，并将允许开发新的抗肿瘤药物 预防心肌感染和中风的血栓治疗。

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. RELEVANCE (See instructions): 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.