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Biophysical Analysis of GPIb-VWF Interaction

GPIb-VWF 相互作用的生物物理分析

基本信息

批准号：
8206779
负责人：
Cheng Zhu
金额：
$ 36.46万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2013-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The objective of this proposal is to elucidate the molecular and biophysical mechanisms that regulate platelet adhesion to disrupted vessel wall at sites of injury. The focus is the interaction of the platelet glycoprotein Ib (GPIb) with plasma protein von Willebrand factor (VWF) that is bound to collagen on subendothelial extracellular matrix. The GPIb-VWF interaction mediates the initial step of the multistep adhesion and signaling cascade, which includes platelet tethering to and rolling (or translocating) on disrupted vascular surfaces. Regulation of this initial adhesion process is crucial: Insufficient adhesion cannot stop bleeding to maintain hemostasis. Excessive adhesion results in thrombosis. Our hypothesis is that initial platelet adhesion is regulated by the interplay of biophysical parameters of the blood flow with specific kinetic and mechanical properties of the GPIb-VWF interaction. Mutations in GPIb and VWF, such as those naturally occurring in patients with various types of von Willebrand diseases (VWD), alter these kinetic and mechanical properties as well as their regulation by biophysical parameters, thereby changing platelet adhesion and resulting in thrombotic or bleeding disorders. Using combined experimental, computational, and theoretical approaches, this hypothesis will be tested in three integrated specific aims: 1) Quantify the regulation of GPIb-VWF interaction by biophysical parameters, 2) Determine the regulation of GPIb-VWF interaction by structural variations, and 3) Investigate GPIb-VWF interaction by molecular dynamics simulations. This integrated and systematic study will clarify how the kinetic and mechanical properties of GPIb-VWF interaction fulfill the biophysical requirements for platelets to adhere to blood vessel wall in the mechanically stressful environment of the circulation. Decoding how molecular structure determines these properties and their regulation by biophysical parameters will provide key insights into vascular physiology and pathology. As a result, the data may offer new therapeutic approaches to inhibiting pathological platelet adhesion during thrombosis and/or intervention to the bleeding disorder. We propose to elucidate the biophysical mechanisms that regulate the molecular interaction of the platelet glycoprotein Ib (GPIb) with protein von Willebrand factor, which mediates platelet adhesion to disrupted vessel wall at sites of injury. This regulation is crucial because insufficient adhesion cannot stop bleeding to maintain hemostasis but excessive adhesion results in thrombosis. The data may offer new therapeutic approaches to inhibiting pathological platelet adhesion during thrombosis and/or intervention to the bleeding disorder von Willebrand diseases.

描述（由申请人提供）：本提案的目的是阐明在损伤部位调节血小板粘附到受损血管壁的分子和生物物理机制。重点是血小板糖蛋白Ib （GPIb）与血浆蛋白von Willebrand factor （VWF）的相互作用，VWF与内皮下细胞外基质上的胶原结合。GPIb-VWF相互作用介导了多步粘附和信号级联的第一步，其中包括血小板在受损血管表面的粘附和滚动（或移位）。对这个初始粘连过程的调节是至关重要的：粘连不足不能止血以维持止血。过度粘连导致血栓形成。我们的假设是，初始血小板粘附是由血流的生物物理参数与GPIb-VWF相互作用的特定动力学和力学特性的相互作用调节的。GPIb和VWF的突变，如在各种类型的血管性血友病（VWD）患者中自然发生的突变，改变了这些动力学和力学特性以及它们通过生物物理参数的调节，从而改变血小板粘附并导致血栓性或出血性疾病。采用实验、计算和理论相结合的方法，该假设将在三个综合的具体目标中得到验证：1)通过生物物理参数量化GPIb-VWF相互作用的调控；2)通过结构变化确定GPIb-VWF相互作用的调控；3)通过分子动力学模拟研究GPIb-VWF相互作用。这项综合和系统的研究将阐明GPIb-VWF相互作用的动力学和力学特性如何满足血小板在循环的机械压力环境中粘附血管壁的生物物理要求。解码分子结构如何决定这些特性及其通过生物物理参数的调节将为血管生理学和病理学提供关键见解。因此，这些数据可能为血栓形成和/或出血障碍干预期间抑制病理性血小板粘附提供新的治疗方法。