Roles of Platelet Glycoproteins and Glycans on Platelet Reactivity and Cardiovasc

血小板糖蛋白和聚糖对血小板反应性和心血管的作用

• 批准号: 8183674
• 负责人: Hui Zhang
• 金额: $ 32.8万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8183674
• 关键词: Adhesions; Affinity; Affinity Chromatography; American; Arterial Fatty Streak; Aspirin; Binding; Biological Assay; Blood Platelets; Blood Vessels; Blood flow; Carbohydrates; Cardiovascular Diseases; Cardiovascular system; Cell Line; Cell surface; Cessation of life; Chemicals; Collagen; Collagen Receptors; Complex; Coronary Arteriosclerosis; Development; Disease; Dose; Endothelium; Enzyme-Linked Immunosorbent Assay; Equal Protection; Event; Future; Glycoconjugates; Glycoproteins; Immobilization; Immunosorbents; In Vitro; Individual; Infection; Injury; Instruction; Integrins; Ischemic Stroke; Lead; Lectin; Link; Mass Spectrum Analysis; Mediating; Membrane Glycoproteins; Metabolic; Methods; Modification; Monitor; Myocardial; Myocardial Infarction; Pathologic; Pathology; Pharmaceutical Preparations; Platelet Activation; Platelet Glycoproteins; Platelet aggregation; Polysaccharides; Prevention; Principal Investigator; Proteins; Reaction; Reagent; Receptor Inhibition; Recombinant Proteins; Residual state; Risk; Role; Rupture; Secure; Stroke; Surface; Techniques; Technology; Thrombosis; Thrombus; Woman; Work; base; design; drug development; glycosylation; men; mouse model; novel; overexpression; prevent; protective effect; receptor; research study; response; sugar

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.

说明）： 血小板活化在心肌梗死（MI）和缺血性卒中中的病理参与是很好的- 确立了习胶原蛋白是一种有效的血小板激活剂，在破坏血小板后，它会暴露于流动的血液中。 血管损伤或动脉粥样硬化斑块破裂后发生的内皮表面。血小板介 血栓形成是MI和中风的直接病理原因，抗血小板治疗是预防MI和中风的有效方法。 主要和次要心血管预防的支柱。低剂量阿司匹林治疗可降低 MI、中风和心血管疾病死亡率降低22-25%;然而，并非所有人都接受了同样的治疗。 阿司匹林的保护越来越多的证据表明，阿司匹林治疗的个体， 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。 血小板在其表面表达几种糖蛋白，作为胶原蛋白受体，包括 糖蛋白Ia和IIa、糖蛋白IV和糖蛋白VI，它们是新的抗- 血小板治疗最近的研究表明，这些糖蛋白受体的表达和它们的功能都可能与糖尿病的发病有关。 糖基化有助于与胶原蛋白结合和血小板反应性。然而，这些结构的基础 糖蛋白修饰及其改变血小板功能的机制尚不清楚， 表征了 本提案的目的是使用新兴的糖蛋白组学和糖组学技术来鉴定 血小板糖蛋白和聚糖的特异性改变，导致血小板反应性升高， 利用这一信息来设计新的抗血栓药物， 治疗心血管疾病有四个具体目标：1）表征 与阿司匹林引起的血小板反应性的高低有关; 2）验证 在独立研究中使用互补技术的糖蛋白和聚糖; 3）评估 体外胶原粘附和血小板反应性中的候选糖蛋白和聚糖;以及，4） 使用小鼠模型确定特定糖蛋白和聚糖对血小板反应性的贡献。 相关性（参见说明）： 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在个体之间存在差异，并将允许开发新的抗- 血栓治疗，以防止心肌感染和中风。