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: 7493838
• 负责人: SAMUEL SANTORO
• 金额: $ 42.48万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7493838
• 关键词: Acute; Address; Adhesions; Agreement; Animals; Anticoagulants; Arteries; Biochemical; Biological Assay; Blood Platelets; Blood Vessels; Cardiac; Cardiac Catheterization Procedures; Cardiac Surgery procedures; Cells; Chronic; Clinical; Collagen; Collagen Receptors; Complex; Cytoplasmic Granules; DNA; Development; Diabetic Retinopathy; Disease; Epidemiologic Studies; Exhibits; Fibrillar Collagen; Genes; Genetic Polymorphism; Glycoproteins; Hemorrhage; Hemostatic Agents; Human; Hybrids; Injury; Integrin alpha2; Integrin alpha2beta1; Integrins; Invasive; Laboratories; Link; Mediating; Mediator of activation protein; Modeling; Mus; Myocardial Infarction; Nature; Obesity; Outcome; PTGS2 gene; Patients; Pharmaceutical Preparations; Phenotype; Plasminogen Activator Inhibitor 1; Platelet Activation; Platelet aggregation; Population; Principal Investigator; Procedures; Process; Proteomics; Relative (related person); Risk Factors; Role; Signal Transduction; Site; Smoking Status; Stroke; Surface; Testing; Thrombosis; Transgenic Mice; Transgenic Organisms; Variant; clinically relevant; concept; in vivo; inhibitor/antagonist; mouse model; mutant; programs; receptor; response; von Willebrand Disease

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容易形成血栓的大分子成分。最近进行的研究 多个实验室（包括申请人的许多实验室）已鉴定出两种不同的血小板表面胶原蛋白 受体、α2β1 整合素和糖蛋白 (GP) VI 复合物。现在一致认为，如申请人最初提出的，这两种受体通过两步、两位点机制介导血小板-胶原相互作用。然而，这两种受体对整个过程的相对贡献，甚至这两个步骤的顺序，都存在着激烈的争论。最近开发的α2β1整联蛋白缺陷型小鼠、GP V1缺陷型小鼠以及适当的测定和动物血栓形成模型现在为明确解决这两种受体的作用和贡献提供了第一个明确的机会。目标 1 将采用细胞生物学、生化、蛋白质组学和体内方法来定义 α2β1 整联蛋白和 GPVI 对血小板与胶原蛋白粘附、胶原蛋白诱导的血小板信号传导和激活以及对急性血管损伤的反应的单独、相加和协同作用。这一目标还将使用转基因小鼠和源自它们的血小板来测试关于α2β1整合素的“激活表型”的两个关键假设，这些小鼠表达表现出“激活表型”的突变α2整合素亚基。积累的流行病学证据表明，α2β1整合素的血小板表面高水平表达是心肌梗塞的独立危险因素。目标 2 将使用自发性心肌梗塞的小鼠模型，该模型是由于转基因过度表达稳定的活性变体而引起的 人 PAI-1（纤溶酶原激活剂抑制剂-1）是人类心肌梗死的既定危险因素， 通过实验确定了 α2β1 整合素和 GPVI 单独和组合在心肌梗死中的作用。 目标三将血小板表面α2β1整合素表达的作用扩展到人类，在新建立的混合心导管插入术/心脏手术套件中接受侵入性手术的患者中，血小板表面α2β1整合素表达作为血栓形成和/或出血并发症的危险因素。该目的将测试与血小板上 α2β1 整合素表达水平相关的 DNA 多态性与出血或血栓表现和并发症等临床结果的关联。