PLATELET SURFACE COLLAGEN RECEPTORS AND THROMBOSIS

血小板表面胶原蛋白受体和血栓形成

• 批准号: 7250517
• 负责人: SAMUEL SANTORO
• 金额: $ 40.96万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-20 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7250517
• 关键词: biological signal transduction; blood pressure; cellular pathology; clinical research; collagen; disease /disorder etiology; disease /disorder model; echocardiography; genetic polymorphism; genetic susceptibility; genetically modified animals; heart catheterization; human subject; insulin sensitivity /resistance; integrins; laboratory mouse; membrane proteins; molecular pathology; myocardial infarction; noninsulin dependent diabetes mellitus; phenotype; platelet activation; platelet aggregation; protein deficiency; protein structure function; proteomics; receptor expression; thrombosis

Collagens are the most thrombogenic macromolecular constituents of the blood vessel wall. Recent studies carried out in several laboratories, including many by the applicant, have identified two distinct platelet surface collagen receptors, the alpha2beta1 integrin and the glycoprotein (GP) VI complex. There is now agreement that the two receptors mediate platelet-collagen interactions via a two-step, two-site mechanism, as originally proposed by the applicant. However, the relative contributions of the two receptors to the overall process, and even the order of the two steps, is intensely debated. The recent development of the alpha2beta1 integrin-deficient mouse, the GP Vl-deficient mouse and appropriate assays and animal thrombosis models now affords the first unambiguous opportunity to address definitively the roles and contributions of the two receptors. Aim 1 will employ cell biologic, biochemical, proteomic and in vivo approaches to define the separate, additive and synergistic contributions of the alpha2beta1 integrin and GPVI to platelet adhesion to collagen, collagen-induced platelet signaling and activation and the response to acute vascular injury. This aim will also test two critical hypotheses regarding the "activated phenotype" of the alpha2beta1 integrin using transgenic mice and platelets derived from them that express a mutant alpha2 integrin subunit that exhibits the "activated phenotype". Accumulated epidemiologic evidence suggests that high level platelet surface expression of the alpha2beta1 integrin is an independent risk factor for myocardial infarction. Aim 2 will use a mouse model of spontaneous myocardial infarction due to the transgenic over expression of a stable, active variant of human PAI-1 (plasminogen activator inhibitor-1), an established risk factor for myocardial infarction in humans, to experimentally define the role(s) of the alpha2beta1 integrin and GPVI alone and in combination in myocardial infarction. Aim three extends to the human the role of platelet surface alpha2beta1 integrin expression as a risk factor for thrombotic and/or bleeding complications in patients undergoing invasive procedures in the newly established hybrid cardiac catheterization/cardiac surgery suite. This aim will test the association of DNA polymorphisms linked to the level of alpha2beta1 integrin expression on platelets with clinical outcome in terms of bleeding or thrombotic manifestations and complications.

胶原蛋白是血管壁中最大的大分子分子成分。最近的研究进行了 在几个实验室中，包括申请人在内的许多实验室，已经确定了两个不同的血小板胶原蛋白 受体，α2BETA1整合素和糖蛋白（GP）VI复合物。现在达成共识，两个受体通过申请人最初提出的两步，两点机制介导血小板 - 胶原蛋白的相互作用。但是，两种受体对整个过程的相对贡献，甚至是两个步骤的顺序，都在激烈争议。 alpha2beta1整联蛋白缺陷的小鼠，GP VL缺陷小鼠以及适当的测定和动物血栓形成模型的最新发展为确定性地解决了两个受体的作用和贡献。 AIM 1将采用细胞生物学，生化，蛋白质组学和体内方法来定义alpha2beta1整合素和GPVI对胶原蛋白，胶原蛋白诱导的血小板信号传导和激活以及对急性血管造成的反应的血小板粘附的单独，添加剂和协同作用。该目标还将使用转基因小鼠和来自它们的血小板来检验有关α2Beta1整联蛋白的“激活表型”的两个关键假设，这些小鼠和血小板表达了一个突变的alpha2整合素亚基，该突变型alpha2整合素亚基表现出“活化表型”。累积的流行病学证据表明，α2Beta1整合素的高水平血小板表面表达是心肌梗塞的独立危险因素。 AIM 2将使用自发心肌梗死的小鼠模型，这是由于稳定的活性变体的转基因而导致的 人PAI-1（纤溶酶原激活物抑制剂1），是人类心肌梗塞的确定危险因素， 实验性地定义了单独的α2Beta1整合素和GPVI的作用，并在心肌梗塞中结合使用。 AIM三扩展到人类的血小板表面α2Beta1整合素表达作为在新建立的杂交心脏导管/心脏插管手术套件中接受侵入性手术的患者中血栓形成和/或出血并发症的危险因素。该目标将测试与血小板上α2Beta1整合素表达水平有关的DNA多态性与临床结果相关的，就出血或血小板表现和并发症而言。