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Thrombin signaling in Hemostatis and thrombosis

止血和血栓形成中的凝血酶信号传导

基本信息

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
项目类别：
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

项目摘要

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是如何调节细胞行为的