Regulation of Platelet Integrin Signaling in Hemostasis and Thrombosis

止血和血栓形成中血小板整合素信号传导的调节

• 批准号: 8421338
• 负责人: Brian G Petrich
• 金额: $ 33.2万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8421338
• 关键词: Actins; Adhesions; Affect; Affinity; Agonist; Anemia; Animals; Antibodies; Binding; Binding Proteins; Biological; Biological Assay; Biological Process; Blood Platelets; Blood Vessels; Blood capillaries; Carotid Artery Injuries; Cell Communication; Cell membrane; Cells; Clot retraction; Collaborations; Collagen; Cytoplasmic Tail; Cytoskeleton; Development; Disease; Endothelial Cells; Failure; Fibrin; Fibrinogen; Fluorescence Microscopy; Hemorrhage; Hemostatic function; Integrins; Kinetics; Lasers; Lead; Letters; Ligand Binding; Ligands; Link; Liquid substance; Measures; Mechanics; Membrane; Mesentery; Mission; Modeling; Molecular; Molecular Genetics; Monitor; Mus; Mutant Strains Mice; Mutation; Myocardial Infarction; National Heart, Lung, and Blood Institute; Pattern; Phenotype; Phosphorylation; Platelet aggregation; Prevention; Prevention therapy; Proteins; Pulmonary Embolism; Recruitment Activity; Regulation; Signal Pathway; Signal Transduction; Stimulus; Stroke; Sum; Tail; Talin; Testing; Therapeutic; Thrombin; Thrombosis; Thrombus; Ursidae Family; Weight; Wild Type Mouse; Work; arteriole; base; capillary; extracellular; ferric chloride; gastrointestinal; in vivo; insight; intravital microscopy; mutant; new therapeutic target; novel; protein function; public health relevance; research study; response

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.

描述（由申请人提供）：血小板中整合素对细胞外配体的亲和力受到严格调节。在破坏血管完整性时，血小板整联蛋白经历构象变化，导致对配体的亲和力增加，称为整联蛋白活化，从而支持止血所需的血小板粘附、聚集和血栓形成。不能适当调节血小板中整合素活性可促进血栓性疾病。该项目的重点是调节talin整合素的相互作用的理由，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。这一概念将在目标1中通过分析表达talin 1突变体的小鼠进行测试，所述突变体选择性地破坏talin激活整合素的能力，而不影响tain与整合素或其他已知的talin结合蛋白在体内的结合。目标2将研究细胞和 分子机制，主要集中在双向整联蛋白信号传导，其是Aim 1中表征的表型的基础。在目标3中，将描述talin和kindlin的细胞分布。 通过荧光显微镜检查血小板，并将剖析调节talin和kindlin再分布到质膜的信号通路。总之，这些研究将提供新的信息整合素-talin相互作用的止血和血栓形成的生物学意义，并提供深入了解的信号转导途径，调节血小板激动剂诱导的动态再分布的蛋白质，控制整合素活化。总之，我们提出的实验，符合NHLBI的使命，可能指向预防和治疗心脏病发作和中风的新疗法。