REGULATION OF PLATELET-ENDOTHELIAL INTERACTIONS

血小板-内皮相互作用的调节

• 批准号: 2218016
• 负责人: Andrew I Schafer
• 金额: $ 24.83万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2218016
• 关键词: G protein; SDS polyacrylamide gel electrophoresis; aspirin; biological signal transduction; blood circulation; blood proteins; blood viscosity; cell cell interaction; erythrocytes; human tissue; ion exchange chromatography; mechanical stress; neutrophil; phorbols; phospholipase C; platelet activation; platelet aggregation; protein kinase C; stimulant /agonist; thin layer chromatography; thromboxanes; vascular endothelium; von Willebrand factor

Following vascular injury, platelet activation and thrombin generation occur in concert in a mutually amplifying scheme to promote the rapid and localized formation of a hemostatic plug. While the important role of platelets in coagulation is now established, interactions between platelets and the fibrinolytic system during clot dissolution have not been elucidated. Studies performed in this laboratory during the previous project period have shown that the fibrinolytic protease plasmin regulates platelet activation in a complex manner that is distinct from the actions of the coagulation protease thrombin. Furthermore, preliminary experiments have shown that plasmin also exerts different actions on vascular endothelial cells (EC). The aim of this proposal is to investigate in detail the effects of plasmin and the fibrinolytic system on platelets and cultured vascular cells. Hypotheses to explain the complex actions of plasmin on platelets and EC will be pursued by examining the sequence and causal relationships of biochemical events in signal transduction induced by plasmin, and comparing and contrasting these events with those induced by the coagulation protease thrombin as well as other platelet and EC agonists. Studies will specifically focus on the control of phospholipid composition and turnover, protein kinase C activation and arachidonic acid metabolism. Biochemical mechanism of platelet and EC deactivation following stimulation by plasmin and other agonists by negative termination signals will be examined, an area of research in cellular signal- response coupling that has received little attention. Evidence for possibly selective actions of plasmin on the G proteins of adenylate cyclase will be followed with detailed studies of the control of the plasmin effect on platelets and EC by cyclic nucleotides. Preliminary evidence for synergistic inhibitory effects of plasmin and prostacyclin on platelet activation, a potentially important new platelet-EC interaction in controlling hemostasis and clot dissolution, will lead to studies of basic mechanisms of previously unknown synergistic inhibitory signaling pathways in platelets and EC. Studies of the regulation of EC function by plasmin will examine not only blood vessels as targets for actions of the fibrinolytic system but also elucidate basic biochemical mechanisms of signal transduction in vascular cells which are largely unknown. Understanding the modulation of platelet and EC actions and interactions by the fibrinolytic system will have pathophysiologic and pharmacologic importance in clarifying our concepts of thrombosis and hemostasis.

血管损伤，血小板激活和凝血酶 在相互放大方案中共同发生生成 促进止血塞的快速和局部形成。 虽然现在血小板在凝结中的重要作用是 建立的血小板与纤维蛋白水解之间的相互作用 凝块溶解过程中的系统尚未阐明。 研究 在上一个项目期间在该实验室进行 已经表明纤维蛋白蛋白酶纤溶酶调节 血小板激活以复杂的方式与 凝血蛋白酶凝血酶的作用。 此外， 初步实验表明纤溶酶也施加 对血管内皮细胞（EC）的不同作用。 目的 该建议是详细研究纤溶酶和 血小板和培养的血管细胞上的纤维蛋白水解系统。 假设解释纤溶酶在血小板上的复杂作用 将通过检查序列和因果关系来追求EC 信号转导中的生化事件的关系 通过纤溶酶，将这些事件与 那些由凝血蛋白酶凝血酶以及 其他血小板和EC激动剂。 研究将特别关注 控制磷脂组成和周转，蛋白质的控制 激酶C活化和花生四烯酸代谢。 血小板和EC失活的生化机制之后 纤溶酶和其他激动剂通过负终止刺激 将检查信号，这是细胞信号研究领域 响应耦合很少受到关注。 证据 纤溶酶在G蛋白上的选择性作用可能 腺苷酸环化酶将随后进行详细研究 控制纤溶酶对血小板的影响和循环控制EC 核苷酸。 协同抑制的初步证据 纤溶酶和前列环素对血小板激活的影响，A 控制的潜在重要的新血小板相互作用 止血和凝块溶解将导致基本的研究 以前未知的协同抑制信号传导的机制 血小板和EC中的途径。 研究EC调节的研究 纤溶酶功能不仅会检查血管作为靶标 用于纤维蛋白水解系统的作用，但也阐明了基本 血管细胞信号转导的生化机制 这在很大程度上未知。 了解调制 血小板和EC的作用以及纤维蛋白水解的相互作用 系统将具有病理生理和药理学的重要性 在澄清我们的血栓形成和止血的概念时。