Role of Von Willebrand Factor in Platelet Thrombosis Formation

血管性血友病因子在血小板血栓形成中的作用

• 批准号: 7995814
• 负责人: Zaverio M Ruggeri
• 金额: $ 53.67万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7995814
• 关键词: Acute; Address; Adhesions; Adhesives; Animals; Binding; Bleeding time procedure; Blood; Blood Platelets; Blood Vessels; Blood flow; Clinical; Collaborations; Collagen; Complex; Data; Development; Diagnosis; Disease; Elements; Event; Exhibits; Funding; Gene Mutation; Glycoproteins; Goals; Hemostatic function; Human; Immune system; Immunoglobulin G; Indium; Injury; Lead; Length; Link; Measures; Mediating; Membrane; Modeling; Molecular; Mouse Strains; Mus; Mutation; Nature; Physiological; Plasma; Platelet Activation; Platelet aggregation; Play; Population; Process; Property; Proteins; Proteolysis; Publishing; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Solutions; Structure; Surface; Tail; Testing; Thrombin; Thrombosis; Thrombus; Vascular Diseases; atherothrombosis; base; cross reactivity; design; dimer; improved; in vivo; in vivo Model; novel; physical state; receptor; research study; response; shear stress; stem; von Willebrand Factor

In this application we propose to continue efforts aimed at elucidating von Willebrand factor (VWF) structure and function focusing on four aims. In aim 1 we will test whether structural elements in the VWF Al domain (VWFA1) can differentially regulate specific adhesive properties. Preliminary data indicate that the interaction of glycoprotein (GP) Iba with VWFA1 immobilized onto a surface, leading to platelet adhesion, may occur through different mechanisms as compared to binding of soluble VWF mediating platelet aggregation. Our goal is to define the distinctive structural elements underlying the initiation and regulation of specific VWF activities and establish their functional relevance in models of vascular injury. In aim 2 we intend to ascertain whether a-thrombin can act as a physiologic modulator of VWF adhesive properties. We hypothesize that VWFA1 and a-thrombin establish inter-molecular contacts when bound to the same GPIba receptor, and this may influence the stability of the VWFA1-GPIba bond independently of shear stress. We propose to identify the VWFA1 residues that support the interaction with a-thrombin bound to GPIba, thus defining a novel mechanism for the regulation of VWF function during thrombogenesis. In aim 3 we propose to evaluate whether a specific IgG found in the human population is a modulator of VWF activity. We have identified in human and mouse blood a specific IgG that binds selectively to VWFA1, and obtained preliminary evidence that this IgG may play a role in thrombus formation. Our goal is to characterize the structure of the specific IgG, define the mode of interaction with VWFA1 and obtain definitive in vivo evidence for its physiopathological significance. In aim 4 we will define the signaling function of collagen-bound VWF leading to platelet activation. We have characterized distinct intracytoplasmic Ca++ signals that follow platelet adhesion to immobilized VWFA1 or collagen under flow conditions, and found that they are enhanced when platelets interact with collagen-bound VWF. We propose to dissect the mechanisms of platelet activation supported by the collagen-VWF complex and the effects of hydrodynamic force on the process. The results of this research will improve our ability to influence disease processes that involve platelets in atherothrombosis.

在此应用中，我们建议继续旨在阐明von Willebrand因素（VWF）结构的努力 功能集中在四个目标上。在AIM 1中，我们将测试VWF Al域中的结构元素是否 （VWFA1）可以差异地调节特定的粘合特性。初步数据表明相互作用 糖蛋白（GP）IBA的vWFA1固定在表面上，可能导致血小板粘附 通过与可溶性VWF介导血小板聚集的结合相比，通过不同的机制。我们的 目标是定义特定vWF启动和调节的基础的独特结构元素 活动并在血管损伤模型中建立功能相关性。在AIM 2中，我们打算确定 A-凝血酶是否可以充当VWF粘合剂特性的生理调节剂。我们假设这一点 当与同一GPIBA受体结合时，VWFA1和A-凝血酶建立分子间接触，这 可能会独立于剪切应力影响VWFA1-GPIBA键的稳定性。我们建议确定 支持与a-凝血酶结合的与gpiba相互作用的VWFA1残基，从而定义了一种新颖的 在血栓形成过程中调节VWF功能的机制。在AIM 3中，我们建议评估 在人口中发现的特定IgG是否是VWF活动的调节剂。我们已经确定 人和小鼠血液有选择地结合VWFA1并获得初步证据的特异性IgG 该IgG可能在血栓形成中发挥作用。我们的目标是表征特定的结构 IgG，定义与VWFA1的相互作用的模式，并获得其生理病理学的确定性证据 意义。在AIM 4中，我们将定义胶原结合vWF的信号传导函数，导致 血小板激活。我们已经表征了遵循血小板粘附的独特内部胞浆内Ca ++信号 在流动条件下固定的VWFA1或胶原蛋白，发现血小板会增强 与胶原结合的VWF相互作用。我们建议剖析由由血小板激活的机理 胶原蛋白-VWF复合物以及流体力学对过程的影响。结果的结果 研究将提高我们影响涉及血小板中血小板的疾病过程的能力。