PAR-1和整合素αIIbβ3是血小板活化和血栓形成中最为重要的受体。αIIbβ3可以结合PAR-1受体的配体凝血酶原和proMMP-1。我们最近发表的研究已证明ADP刺激可引起αIIbβ3上结合的凝血酶原激活形成凝血酶，后者可切割PAR-1受体引起不可逆的血小板聚集。在此基础上的预实验又发现了αIIbβ3上所结合的PAR-1配体呈现刺激剂依赖性的激活，从而可能对不同刺激剂所导致的血小板活化起到特异性的支持作用。本项目拟从胞外刺激剂的选择性和胞内信号的转导机制两方面着手，深入研究凝血酶原和proMMP-1与αIIbβ3的解离活化机制，寻找它们的关键结合位点，并阐明它们的解离活化在血小板持续激活和血栓形成中的作用。我们期望为血小板的活化机制提供新的理论补充，并为新型抗血栓分子靶点的研发开拓新的思路。

PAR-1 and integrin αIIbβ3 are among the most important receptors in platelet activation and thrombosis. αIIbβ3 is capable of binding prothrombin and proMMP-1, two PAR-1 ligand precursors. Our recent publication confirmed that ADP stimulation could induce αIIbβ3-associated prothrombin activation and the formation of thrombin. Subsequent activation of PAR-1 is indispensable for ADP induced irreversible platelet aggregation. Continue on this line, we recently found αIIbβ3-associated PAR-1 ligand precursors could be agonist-specific activated, and thus constitute a previously unappreciated important yet specific supporting system in different platelet activation senario. We thus aim to clarify the disassociation and activation mechanisms of PAR-1 ligand precursors from αIIbβ3, their signaling dependence on different agonists, as well as their functions in thrombosis and haemostasis. We also aim to mapping the binding site of prothrombin/proMMP-1 and αIIbβ3, which could lay basis for the development of future interventin reagents. This project will strengthen the understanding of molecular mechanism of platelet activation and provide basis for developing novel therapeutic targets of anti-thrombotic diseases.