Thrombin signaling in Hemostatis and thrombosis

止血和血栓形成中的凝血酶信号传导

• 批准号: 7535006
• 负责人: SHAUN R. COUGHLIN
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-05 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7535006
• 关键词: Ablation; Accounting; Adhesions; Alleles; Anticoagulants; Anticoagulation; Antiplatelet Drugs; Behavior; Blood Platelets; Cells; Clinical Research; Coagulation Process; Collagen; Endothelial Cells; Endotoxemia; Factor IX; Fibrin; Fibrinogen; Future; Generations; Genetic; Goals; Grant; Hematopoietic; Hemostatic Agents; Hemostatic function; Human; Inflammation; Injury; Knock-out; Laboratories; Lasers; Link; Mediator of activation protein; Modeling; Mus; Mutation; PAWR gene; Pathway interactions; Peptide Hydrolases; Pharmacia brand of estropipate; Platelet Activation; Platelet aggregation; Prevention; Process; Proteinase-Activated Receptors; Publishing; Reaction; Receptor Signaling; Relative (related person); Research Personnel; Role; Signal Transduction; Site; Source; Stress; System; Testing; Thinking; Thrombin; Thromboembolism; Thromboplastin; Thrombosis; Thrombus; Tissues; VWF gene; Wild Type Mouse; Work; hematopoietic tissue; in vivo; mouse model; postnatal; programs; receptor; response

A central goal of my laboratory has been to determine how thrombin regulates cellular behaviors involved in hemostasis, thrombosis, inflammation and other processes, and to elucidate the roles of thrombin signaling in vivo. This grant has focused on hemostasis and thrombosis. Our previous work showed that protease- activated receptors (PARs) are necessary for platelet activation by thrombin and important for thrombosis and hemostasis in mouse models. These and other studies support exploration of PAR antagonism for the prevention or treatment of thrombosis in humans. We now propose studies to define the roles of PARs in more detail and to determine how thrombin signaling integrates with other platelet activation and coagulation mechanisms in vivo. We shall ask:1) Are vWF, collagen and thrombin the major initiators of platelet activation in vivo? How do these pathways interact? Using sophisticated mouse models, we will test the hypothesis that GPIb and GP-VI signaling is necessary and sufficient to drive platelet adhesion and juxtamural thrombus formation at a site of injury but that PAR signalingis necessary for propagation of the thrombus away from the vessel wall. Genetic and pharmacological approaches will be used. PAR interactions with P2Y12 and Tbxa2r (TP) will also be probed. 2) How do thrombin-inducedplatelet activation and fibrin formation interact in hemostasis and thrombosis? Does their relative importance change when thrombin generation or activity is reduced or inhibited? We shall determine whether platelet activation by thrombin is important for propagation of thrombin generation and fibrin formation away from the vessel wall. We shall also ask whether disruption of PAR signalingin the setting of low thrombin generation has synergistic effects on thrombosis or hemostasis. 3) What is the role of tissue factor expression in endothelial and hematopoietic cells in hemostasis and thrombosis? In endotoxemia? Can roles for such tissue factor be uncovered or amplified by knockout of alternative mechanisms for propagation of coagulation? Tissue factor expression will be ablated in endothelial and hematopoietic tissues to probe the source and roles of "circulatingtissue factor". These studies will illuminate how key effectors of hemostasis and thrombosis interact.

我实验室的一个中心目标是确定凝血酶如何调节参与的细胞行为 止血、血栓形成、炎症和其他过程，并阐明凝血酶信号传导在 体内。这笔赠款主要用于止血和血栓形成。我们之前的工作表明，蛋白酶- 激活受体（PAR）是凝血酶激活血小板所必需的，对于血栓形成和血栓形成也很重要。 小鼠模型中的止血。这些和其他研究支持对 PAR 拮抗作用的探索 预防或治疗人类血栓形成。我们现在提出研究来定义 PAR 在 更多细节并确定凝血酶信号传导如何与其他血小板活化和凝血整合 体内机制。我们要问：1）vWF、胶原蛋白和凝血酶是血小板的主要引发剂吗？ 体内激活？这些途径如何相互作用？使用复杂的鼠标模型，我们将测试 假设 GPIb 和 GP-VI 信号传导对于驱动血小板粘附是必要且充分的 损伤部位近壁血栓形成，但 PAR 信号传导对于血栓的传播是必需的 血栓远离血管壁。将使用遗传和药理学方法。 PAR相互作用 P2Y12 和 Tbxa2r (TP) 也将被探测。 2) 凝血酶如何诱导血小板活化和纤维蛋白 止血和血栓形成相互作用？当凝血酶增加时，它们的相对重要性会改变吗？ 生成或活动减少或抑制？我们将确定凝血酶是否激活血小板 对于远离血管壁的凝血酶生成和纤维蛋白形成的传播很重要。我们将 还询问在凝血酶生成量低的情况下 PAR 信号传导的破坏是否具有协同效应 关于血栓或止血。 3）组织因子表达在内皮和造血中起什么作用 细胞的止血和血栓作用？内毒素血症？这种组织因子的作用是否可以被揭示或 通过敲除凝血传播的替代机制来放大？组织因子表达 将在内皮和造血组织中消融，以探究“循环组织”的来源和作用 这些研究将阐明止血和血栓形成的关键效应物如何相互作用。