Mechanisms of interactions between von Willebrand factor and its binding partners

冯维勒布兰德因子与其结合伙伴之间的相互作用机制

• 批准号: 10629031
• 负责人: Hongxia Fu
• 金额: $ 64.54万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629031
• 关键词: ADAMTS; Adhesions; Atomic Force Microscopy; Behavior; Binding; Biophysics; Blood; Blood Coagulation Disorders; Blood Platelets; Blood Vessels; Coagulation Process; Complex; Data; Disease; Dissociation; Event; Factor VIII; Fibrin; Fluorescence; Fluorescence Microscopy; Goals; Hematological Disease; Hemorrhage; Human; Image; Individual; Infusion procedures; Injury; Intravenous infusion procedures; Label; Laboratories; Left; Link; Location; Magnetism; Maps; Measures; Mediating; Methods; Microfluidics; Microscopy; Modeling; Molecular; Molecular Conformation; Mutation; Patients; Plasma; Polysaccharides; Preparation; Process; Property; Proteins; Reporting; Role; Sampling; Shapes; Spectrum Analysis; Structure; System; Thrombin; Thrombosis; Thrombus; Visualization; Work; body sense; disulfide bond; high risk; imaging modality; immunogenicity; improved; insight; interdisciplinary approach; monomer; nanometer; preservation; prevent; single molecule; structural determinants; superresolution imaging; therapeutic development; von Willebrand Disease; von Willebrand Factor

SUMMARY Von Willebrand factor (VWF) has two major roles in blood. One is to facilitate platelet adhesion and aggregation, in which a critical step is to activate the VWF A1 domain to bind with platelet protein GPIbα under flow. The other is to protect coagulation factor VIII (FVIII) from degradation, which is important for fibrin clot formation. Mutations in VWF interfering with these binding interactions can cause thrombosis or von Willebrand disease. The goal of this project is to determine molecular mechanisms governing the interactions between VWF and its binding partners GPIbα and FVIII. Several questions regarding VWF interactions with GPIbα and FVIII persist. There has not been a consistent model for how VWF A1 domain is activated to bind with GPIbα. It still remains unclear which and how conformational changes actually happen during A1 activation. To date, the interaction between VWF multimer and FVIII has been studied primarily using bulk VWF preparations. How FVIII binds to individual VWF multimers is unknown. In intravenous infusion treatment for bleeding disorders, more free FVIII in the infusion is linked to higher risk of FVIII immunogenicity, but the mechanisms remain unclear. In this project, we will combine single molecule biophysics and super resolution imaging methods to study the following aims. (1) Understand flow-induced activation of VWF A1 binding with GPIbα. (2) Dissect the VWF- FVIII binding mode and its role in protecting FVIII in blood. This study will provide direct evidence for the mechanisms of how VWF binds with GPIbα and FVIII, and provide new insights into therapeutic development to treat thrombotic or bleeding disorders.

概括 血管性血友病因子（VWF）在血液中有两个主要作用，一是促进血小板粘附和促进血小板聚集。 聚集，其中关键的一步是在条件下激活 VWF A1 结构域与血小板蛋白 GPIbα 结合 另一个是保护凝血因子 VIII (FVIII) 免于降解，这对于纤维蛋白凝块很重要。 VWF 的突变干扰这些结合相互作用可能导致血栓形成或血管性血友病。 该项目的目标是确定控制 VWF 之间相互作用的分子机制。 及其结合伙伴 GPIbα 和 FVIII。 关于 VWF 与 GPIbα 和 FVIII 相互作用的几个问题仍然存在。 VWF A1 结构域如何被激活以与 GPIbα 结合的一致模型仍然不清楚。 迄今为止，VWF 多聚体之间的相互作用实际上发生在 A1 激活过程中。 主要使用批量 VWF 制剂研究 FVIII 如何与单个 VWF 多聚体结合。 在治疗出血性疾病的静脉输注中，输注中更多的游离 FVIII 与此有关。 FVIII 免疫原性的风险较高，但其机制仍不清楚。 在这个项目中，我们将结合单分子生物物理学和超分辨率成像方法来研究 (1) 了解流诱导的 VWF A1 与 GPIbα 结合的激活。 本研究将为FVIII结合模式及其在血液中保护FVIII的作用提供直接证据。 VWF 如何与 GPIbα 和 FVIII 结合的机制，并为治疗开发提供新的见解 治疗血栓或出血性疾病。