Regulation of Platelet Integrin Signaling in Hemostasis and Thrombosis

描述（由申请人提供）：整合素对细胞外配体的亲和力在血小板中受到严格调节。当血管完整性被破坏时，血小板整合素发生构象改变，导致对配体的亲和力增加，称为整合素激活，从而支持血小板粘附、聚集和止血所必需的血栓形成。血小板整合素活性调节不当可促进血栓性疾病。这个项目的重点是talin-integrin相互作用的调控，选择性地调节它们的相互作用可以提供一种新的抗血栓治疗策略。这一概念将在Aim 1中进行测试，通过分析表达talin1突变体的小鼠，这些突变体选择性地破坏talin激活整合素的能力，而不影响tin与整合素或其他已知的talin结合蛋白的结合。目的2将研究细胞和

DESCRIPTION (provided by applicant): The affinity of integrins for extracellular ligands is tightly regulated in platelets. Upon disruption of vascular integrity, platelet integrins undergo conformational changes that result in increased affinity for ligand, termed integrin activation, thereby supporting platelet adhesion, aggregation, and thrombus formation necessary for hemostasis. Failure to properly regulate integrin activity in platelets can promote thrombotic disease. This project focuses on the regulation of talin-integrin interactions with the rationale that selectively modulating their interactions could provide a novel anti-thrombotic therapeutic strategy. This concept will be tested in Aim 1 by analyzing mice expressing talin1 mutants that selectively disrupt the capacity of talin to activate integrins without affecting the binding of tain to integrins or other known talin-binding proteins in vivo. Aim 2 will investigate the cellular and molecular mechanisms, focused primarily on bidirectional integrin signaling, that underlie the phenotypes characterized in Aim 1. In Aim 3, the cellular distribution of talin and kindlin will be examined in platelets by fluorescence microscopy and signaling pathways that regulate talin and kindlin redistribution to the plasma membrane will be dissected. Together, these studies will provide new information about the biological significance of integrin-talin interactions in hemostasis and thrombosis and provide insights into the signaling pathways that regulate the platelet agonist-induced dynamic redistribution of proteins that control integrin activation. Together our proposed experiments, consistent with the mission of the NHLBI, may point to novel therapies for the prevention and treatment of heart attack and stroke.