Initiation and Regulation of Platelet Thrombus Formation

描述(申请人提供)：本申请的目的是研究von Willebrand因子(VWF)在血管损伤部位，特别是在以快速血流为特征的循环区域启动血小板沉积中所起的核心作用。其目的是阐明黏附相互作用和细胞反应的机制，这些机制不仅与止血有关，而且与动脉血栓形成引起的常见和严重疾病的发展有关，如心肌梗死和中风。第一个目的是确定VWF A1结构域与血小板糖蛋白(GP)Iba之间形成的键的生物力学特征，这些键与A1结构域的特定结构有关。第二个目的是确定可溶性VWF多聚体和膜系带在稳定GP Iba介导的血小板黏附中的作用机制。这些研究将有助于理解血小板如何导致动脉狭窄的急性闭塞。第三个目的是基于结晶学证据：a-凝血酶可能稳定VWF A1结构域与GP Iba的相互作用，从而可能通过一种独立于血小板激活的机制在调节血小板与血栓形成表面的初始黏附中发挥意想不到的作用。拟议的研究将阐明这种新的α-凝血酶功能的生物学意义和结构基础。第四个目的是描述与VWF A1结构域和GP Iba之间相互作用相关的信号事件，并对这种相互作用促进血小板激活的机制得到更明确的定义。第五个目的是确定VWF如何与细胞外基质成分结合，特别是确定与VI型胶原和蛋白多糖中存在的寡糖相互作用的潜在生物学意义。拟议的研究结果将通过提供有关正常止血和病理性动脉血栓形成的核心过程的新的机制信息，对公众健康产生影响。

DESCRIPTION (provided by applicant): The purpose of this application is to study the central role played by von Willebrand factor (VWF) in initiating platelet deposition at sites of vascular injury, particularly in areas of the circulation characterized by rapid blood flow. The goal is to elucidate the mechanisms of adhesive interactions and cellular responses that are relevant to the arrest of bleeding from wounded tissues but also to the development of common and serious diseases caused by arterial thrombosis, such as myocardial infarction and stroke. The first aim is to define the biomechanical characteristics of the bonds formed between the VWF A1 domain and the platelet glycoprotein (GP) Iba in relation to specific structural aspects of the A1 domain. The second aim is to define the mechanisms through which soluble VWF multimers and membrane tethers contribute to stabilizing platelet adhesion mediated by GP Iba. These studies will be relevant to understand how platelets may precipitate the acute occlusion of stenotic arteries. The third aim is based on the crystallographic evidence: that a-thrombin may stabilize the VWF A1 domain-GP Iba interaction, and may thus play an unexpected role in modulating the initial adhesion of platelets to a thrombogenic surface through a mechanism that is independent of platelet activation. The proposed studies will clarify the biological significance and structural bases of this novel alpha-thrombin function. The fourth aim is to characterize the signaling events related to the interaction between the VWF A1 domain and GP Iba, and obtain a more definitive definition of the mechanisms through which the interaction contributes to platelet activation. The fifth aim is to define how VWF binds to extracellular matrix components, in particular to define the potential biological significance of the interactions with collagen type VI and the oligosaccharides that are present in proteoglycans. The results of the proposed studies will have an impact on public health by providing novel mechanistic information on processes that are central to normal hemostasis and pathological arterial thrombosis.