Platelet glycoprotein V as modulator of hemostasis, thrombosis and thrombo-inflammation

血管损伤部位的血小板活化和凝血是止血的关键，但也会促进血管病理中的血栓形成和炎症。在我们的初步工作中，我们为一种血小板协调机制提供了证据，该机制在最初止血后局部限制过量的纤维蛋白形成，该机制受丰富的血小板糖蛋白(GP)V的集中调节。在血小板激活过程中，GPV被凝血酶切割，我们认为形成的GPV/凝血酶复合体调节凝血酶的定位和纤维蛋白形成活性。在拟议的项目中，我们将使用遗传学和药理学方法来研究GPV-凝血酶相互作用如何调节纤维蛋白形成，从而调节止血、血栓和血栓炎症途径的确切机制。我们将利用新的遗传小鼠模型、重组的可溶性GPV变异体和一组单抗，研究GPV在各种小鼠疾病模型和人类血液中的调节及其(病理)生理活性。这些工具将进一步与先进的显微镜方法相结合，以破译GPV对血栓/纤维蛋白形成的时空调节。通过这些研究，我们期望对凝血酶活性/凝血在止血、血栓形成和血栓性炎症中的血小板依赖性调节有详细的了解，这可能为为有出血、血栓形成或炎性组织损伤风险的患者开发新的治疗策略提供基础。

The activation of platelets and coagulation at vascular injury sites is crucial for hemostasis but can promote thrombosis and inflammation in vascular pathologies. In our preliminary work we have provided evidence for a platelet orchestrated mechanism that locally limits excessive fibrin formation after initial hemostatic platelet deposition that is centrally regulated by the abundant platelet glycoprotein (GP) V. During platelet activation, GPV is cleaved by thrombin and we propose that the formed GPV/thrombin complex modulates thrombin localization and its fibrin-forming activity. In the proposed project, we will use genetic and pharmacological approaches to investigate the exact mechanisms how GPV-thrombin interactions modulate fibrin formation and thus regulate hemostatic, thrombotic and thrombo-inflammatory pathways. Utilizing novel genetic mouse models, recombinant soluble GPV variants and panels of monoclonal antibodies we will study GPV regulation and its (patho-)physiological activity in various murine disease models and in human blood. These tools will further be combined with advanced microscopy methods to decipher the spatio-temporal modulation of thrombus/fibrin formation by GPV. With these studies, we expect to gain a detailed understanding of platelet-dependent modulation of thrombin activity / coagulation in hemostasis, thrombosis and thrombo-inflammation that could provide a basis for the development of new therapeutic strategies for patients at risk of bleeding, thrombosis or inflammatory tissue damage.