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.

总结 血管性血友病因子（VWF）在血液中有两个主要作用。一种是促进血小板粘附， 在血小板聚集过程中，关键步骤是激活VWF A1结构域，使其与血小板蛋白GPIbα结合， 流另一个是保护凝血因子VIII（FVIII）不被降解，这对纤维蛋白凝块很重要 阵VWF中的突变干扰这些结合相互作用可导致血栓形成或血管性血友病 疾病本项目的目标是确定VWF与细胞间相互作用的分子机制。 及其结合伴侣GPIbα和FVIII。 关于VWF与GPIbα和FVIII相互作用的几个问题仍然存在。并未出现 VWF A1结构域如何被激活与GPIbα结合的一致模型。目前仍不清楚是哪一种以及如何进行 构象变化实际上发生在A1激活期间。迄今为止，VWF多聚体之间的相互作用 和FVIII的研究主要使用散装VWF制剂。FVIII如何与单个VWF多聚体结合 不明在出血性疾病的静脉输注治疗中，输注中更多的游离FVIII与以下因素有关： FVIII免疫原性的风险较高，但其机制仍不清楚。 本项目将联合收割机与单分子生物物理学和超分辨成像技术相结合， 以下目标。(1)了解血流诱导的VWF A1与GPIbα结合的激活。(2)解剖VWF- FVIII结合模式及其在保护血液中FVIII中的作用。这项研究将为 VWF如何与GPIbα和FVIII结合的机制，并为治疗开发提供新的见解， 治疗血栓形成或出血性疾病。