Initiation and Regulation of Platelet Thrombus Formation

本申请的目的是研究货车维勒布兰德因子（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中引发血小板沉积中所起的作用。目的是阐明粘附相互作用和细胞反应的机制，这些机制与阻止受伤组织出血有关，也与动脉血栓形成引起的常见和严重疾病（如心肌梗死和中风）的发展有关。第一个目标是定义 VWF A1结构域与血小板结合的生物力学特性 糖蛋白（GP）Ib-α与A1结构域的特定结构方面的关系。第二个目的是确定可溶性VWF多聚体和膜系链有助于稳定GP Ib-α介导的血小板粘附的机制。第三个目的是基于结构证据，即α-凝血酶可以稳定VWF A1结构域-GP Ib-α相互作用，因此可以通过独立于血小板活化的机制在调节血小板与血栓形成表面的初始粘附中发挥意想不到的作用。这些研究将有助于阐明这种新型凝血酶的生物学意义和作用机制 功能第四个目标是表征与以下之间的相互作用相关的信号事件： 的VWF A1域和GP Ib-α，并获得一个更明确的定义的机制，通过这种相互作用有助于血小板活化。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型胶原和蛋白聚糖中存在的寡糖相互作用的潜在生物学意义。与该计划中的所有其他项目以及核心A的广泛互动将促进这些目标的发展。拟议研究的结果将通过提供关于正常止血和病理性动脉血栓形成的核心过程的新机制信息，对公共卫生产生影响。

The purpose of this application is to study the role played by van 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 ilycoprotein (GP) Ib-alpha 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 Ib-alpha. The third aim is based on structural evidence that alpha-thrombin may stabilize the VWF A1 domain-GP Ib-alpha 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 mechanism of this novel athrombin function. The fourth aim is to characterize the signaling events related to the interaction between the VWF A1 domain and GP Ib-alpha, 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. Extensive interactions with all the other projects in the program and with a core A will facilitate the development of these aims. 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.