Initiation and Regulation of Platelet Thrombus Formation

血小板血栓形成的引发和调节

• 批准号: 6811202
• 负责人: Zaverio M Ruggeri
• 金额: $ 31.28万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2005-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6811202
• 关键词: biological signal transduction; biomechanics; calcium flux; cell adhesion; clinical research; collagen; electron crystallography; extracellular matrix proteins; genetically modified animals; glycoproteins; hemodynamics; human subject; laboratory mouse; molecular assembly /self assembly; oligosaccharides; platelet activation; platelet aggregation; protein binding; protein protein interaction; protein structure function; shear stress; surface property; thrombin; thrombosis; von Willebrand factor

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.

描述（由申请人提供）：本申请的目的是研究von Willebrand因子（VWF）在血管损伤部位启动血小板沉积中所起的核心作用，尤其是在以快速血流为特征的循环系统区域。目的是阐明与受伤组织中出血有关的粘附相互作用和细胞反应的机制，也与动脉血栓形成引起的常见和严重疾病（例如心肌梗塞和中风）引起的常见和严重疾病。第一个目的是定义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，相对于A1域的特定结构方面。第二个目的是定义可溶性VWF多聚体和膜系的机制，有助于稳定由GP IBA介导的血小板粘附。这些研究将与了解血小板如何沉淀狭窄动脉的急性阻塞有关。第三个目的是基于晶体学证据：A-凝血酶可以稳定VWF A1域-GP IBA相互作用，因此可能在调节血小板的初始粘附到血小板表面的初始粘附方面发挥了意想不到的作用，该机制独立于血小板激活。拟议的研究将阐明这种新型α-凝血酶功能的生物学意义和结构碱基。第四个目的是表征与VWF A1域和GP IBA之间相互作用相关的信号事件，并获得对相互作用有助于血小板激活的机制的更确定的定义。第五个目的是定义VWF如何与细胞外基质成分结合，特别是为了定义与胶原型VI相互作用的潜在生物学意义，以及蛋白聚糖中存在的寡糖。拟议研究的结果将通过提供有关正常止血和病理动脉血栓形成的过程的新机械信息来影响公共卫生。