GPIb-IX and VWF in thrombosis and thrombocytopenia

GPIb-IX 和 VWF 在血栓形成和血小板减少症中的作用

• 批准号: 10574144
• 负责人: Renhao Li
• 金额: $ 109.55万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2030-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574144
• 关键词: Address; Blood; Blood Platelets; Blood coagulation; Complex; Development; Disease; Functional disorder; Funding; Future; Glycoprotein Ib; Goals; Grant; Hemostatic function; Investigation; Knowledge; Ligands; Mediating; Molecular; Molecular Conformation; Mouse Strains; Mutation; Pathogenesis; Pathology; Physiological; Plasma; Process; Reagent; Regulation; Structure; Surface; Thrombocytopenia; Thrombosis; flexibility; multidisciplinary; novel therapeutics; platelet function; receptor; therapeutic development; thromboinflammation; thrombotic; von Willebrand Factor

PROJECT SUMMARY Understanding the interplay between blood, vessel, and shear flow is key to elucidate the pathophysiology of thrombosis and related diseases. Both glycoprotein (GP)Ib-IX-V complex, an abundant receptor complex on the platelet surface, and its ligand von Willebrand factor (VWF) in the plasma critically mediate hemostasis, thrombosis, and thrombo-inflammation by sensing and responding to blood shear flow. Although much is known about this important receptor-ligand pair, significant knowledge gaps, especially the molecular mechanisms underlying their activation and regulation, have remained open. As the continuation of two current R01 grants entitled “Structure and function of platelet glycoprotein Ib-IX-V complex” and “Conformational activation of von Willebrand factor”, this proposed R35 project seeks to fill several long-standing knowledge gaps and address controversial questions in our understanding of GPIb- IX-V, VWF and related disease pathology. Through systematic, multidisciplinary analysis of inter-domain interactions in GPIb-IX and VWF, we have recently identified the mechanosensory domain (MSD) in GPIb- IX and the discontinuous autoinhibitory module (AIM) in VWF, leading to elucidation of their respective activation mechanisms. In addition to significant implications on pathophysiology of many related thrombotic and thrombocytopenic disorders, these mechanisms provide a coherent conceptual framework for future mechanistic investigations and novel therapeutic development. In this project, we seek to determine the structure of the GPIb-IX complex and VWF domains, resolve the current controversy about the activation mechanism of VWF particularly the AIM conformation, and elucidate mechanisms that regulate activities of GPIb-IX and VWF. To accomplish these goals, we will continue to develop new reagents targeting a key domain, new constructs enabling interdisciplinary analysis, and new mouse strains bearing key mutations to specifically modulate their activity. The seven-year funding period will provide additional flexibility and continuity for pursuing difficult-to-get structures and developing key reagents. Overall, completion of the proposed study will elucidate the fundamental activation and regulation mechanisms of GPIb-IX-V and VWF, significantly advance our understanding of pathogenesis of many thrombotic and thrombocytopenic diseases, and potentially identify new strategies to develop treatments for these diseases.

项目概要 了解血液、血管和剪切流之间的相互作用是阐明病理生理学的关键 血栓形成及相关疾病。糖蛋白 (GP)Ib-IX-V 复合物，丰富的受体 血小板表面的复合物及其血浆中的配体冯维勒布兰德因子（VWF）关键介导 通过感知和响应血液剪切流来止血、血栓形成和血栓炎症。 尽管人们对这一重要的受体-配体对了解很多，但仍存在显着的知识差距，尤其是 它们激活和调节的分子机制仍然是开放的。作为 继续当前两项 R01 资助，题为“血小板糖蛋白 Ib-IX-V 的结构和功能” 复杂”和“冯维勒布兰德因子的构象激活”，这个拟议的 R35 项目旨在填补 一些长期存在的知识差距，并解决了我们对 GPIb 的理解中存在争议的问题 IX-V、VWF 和相关疾病病理学。通过系统的、多学科的跨领域分析 GPIb-IX 和 VWF 之间的相互作用，我们最近发现了 GPIb-IX 中的机械感觉域 (MSD) IX 和 VWF 中的不连续自抑制模块 (AIM)，从而阐明了它们各自的 激活机制。除了对许多相关的病理生理学产生重大影响外， 血栓形成和血小板减少性疾病，这些机制提供了一个连贯的概念框架 用于未来的机制研究和新的治疗开发。在这个项目中，我们力求 确定GPIb-IX复合物和VWF结构域的结构，解决目前关于GPIb-IX复合物和VWF结构域的争议 VWF 的激活机制，特别是 AIM 构象，并阐明其机制 调节 GPIb-IX 和 VWF 的活性。为了实现这些目标，我们将继续开发新的 针对关键领域的试剂、支持跨学科分析的新结构以及新小鼠 带有关键突变的菌株可以特异性调节其活性。七年资助期将 为追求难以获得的结构和开发关键性提供额外的灵活性和连续性 试剂。总体而言，完成拟议的研究将阐明基本的激活和 GPIb-IX-V 和 VWF 的调节机制，显着增进了我们对发病机制的理解 许多血栓和血小板减少性疾病的发病率，并有可能确定新的策略来开发 这些疾病的治疗。