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.

项目总结 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。 血栓形成和相关疾病。糖蛋白(GP)Ib-IX-V复合体，一种丰富的受体 血小板表面复合体及其配体von Willebrand因子(VWF)在血浆中起关键作用 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，但重大的知识差距，特别是 它们的激活和调控的分子机制仍然是开放的。作为 延续R01目前的两项赠款，题为“血小板糖蛋白Ib-IX-V的结构和功能” 复杂“和”von Willebrand因子的构象活化“，这项拟议的R35项目试图填补 几个长期存在的知识差距，并解决我们对GPIB理解中的争议问题- IX-V、VWF及相关疾病病理学。通过系统的、多学科的跨域分析 在GPIB-IX和VWF的相互作用中，我们最近确定了GPIB-IX中的机械感受域(MSD)- IX和VWF中的不连续自身抑制模块(AIM)，从而阐明了它们各自的 激活机制。除了对许多相关疾病的病理生理学有重大影响外 血栓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，我们寻求 确定GPIB-IX复合体和VWF结构域的结构，解决目前关于 VWF的激活机制，特别是AIM构象，并阐明了 调节GPIB-IX和VWF的活动。为了实现这些目标，我们将继续开发新的 以关键领域为目标的试剂，支持跨学科分析的新结构，以及新鼠标 携带关键突变的菌株专门调节其活性。七年的资助期将 为追求难以获得的结构和开发密钥提供额外的灵活性和连续性 试剂。总体而言，拟议研究的完成将阐明基本的激活和 GPIB-IX-V和VWF的调节机制，极大地促进了我们对发病机制的理解 许多血栓性和血小板减少性疾病，并可能确定新的战略来开发 这些疾病的治疗方法。