Biophysical Analysis of GPIb-VWF Interaction

GPIb-VWF 相互作用的生物物理分析

• 批准号: 8024484
• 负责人: Cheng Zhu
• 金额: $ 36.82万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8024484
• 关键词: Adhesions; Binding; Blood Circulation; Blood Platelets; Blood Vessels; Blood flow; Collagen; Data; Disease; Environment; Extracellular Matrix; Glycoprotein Ib; Hemorrhage; Hemostatic function; Injury; Intervention; Kinetics; Mechanics; Mediating; Molecular; Molecular Structure; Mutation; Names; Pathology; Patients; Physiology; Plasma Proteins; Platelet Glycoproteins; Principal Investigator; Property; Proteins; Regulation; Research; Signal Transduction; Site; Surface; Testing; Thrombosis; Variant; adhesion process; insight; molecular dynamics; novel therapeutic intervention; programs; von Willebrand Disease; von Willebrand Factor

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调节血小板粘附至损伤部位破裂血管壁的分子和生物物理机制。重点是血小板糖蛋白Ib（GPIb）与血浆蛋白血管性血友病因子（VWF）的相互作用，该因子与内皮下细胞外基质上的胶原蛋白结合。GPIb-VWF相互作用介导了多步粘附和信号级联的初始步骤，其包括血小板在破裂的血管表面上束缚和滚动（或移位）。调节这种初始粘附过程至关重要：粘附不足无法止血以维持止血。过度粘连导致血栓形成。我们的假设是，初始血小板粘附调节的生物物理参数的血流与特定的动力学和机械性能的GPIb-VWF相互作用的相互作用。GPIb和VWF中的突变，例如在患有各种类型的血管性血友病（VWD）的患者中天然存在的那些突变，改变这些动力学和机械性质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形成或出血性疾病。结合实验，计算和理论方法，这一假设将在三个综合的具体目标进行测试：1）量化的GPIb-VWF相互作用的生物物理参数的调节，2）确定GPIb-VWF相互作用的结构变化的调节，和3）研究GPIb-VWF相互作用的分子动力学模拟。这项综合和系统的研究将阐明GPIb-VWF相互作用的动力学和机械性质如何满足血小板在循环的机械压力环境中粘附于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，这些数据可能提供新的治疗方法来抑制血栓形成期间的病理性血小板粘附和/或对出血性疾病的干预。 我们建议阐明调节血小板糖蛋白Ib（GPIb）与血管性血友病因子（vonWillebrand factor）的分子相互作用的生物物理机制，该因子介导血小板粘附到损伤部位的破裂血管壁。这种调节至关重要，因为粘附不足无法止血以维持止血，但粘附过度会导致血栓形成。这些数据可能提供新的治疗方法，以抑制血栓形成过程中的病理性血小板粘附和/或干预出血性疾病血管性血友病。