Proteins of Blood Coagulation

描述(申请人提供)：这项研究计划的长期目标是增加我们关于血浆蛋白如何与循环中的血小板相互作用的基本知识，从而导致它们在血管损伤部位的激活和形状变化。这些反应在导致人类心脏病和中风的心血管疾病中发挥着重要作用。该方法包括研究凝血酶和von Willebrand因子(VWF)在血小板表面启动的信号传递过程，以及它们与控制血小板形状的细胞骨架蛋白的关系。这些研究将集中在糖蛋白Ib-Lx-V复合体，它与血小板中a，b和g丝蛋白的结合，以及这些丝蛋白与带有DH-PH结构域的鸟嘌呤核苷酸交换因子(Global)的关系。这种被称为丝胺相关蛋白的全球环境基金已经在我们的实验室进行了表征。然后，这些研究将扩展到特定的小GTP酶，如Rho、Rac和CDC42，它们作为GEF的底物，在血小板激活时丝足、片脂、应力纤维和焦点粘连的发展中发挥特殊作用。在平行实验中，将通过小的GTP酶(Rho、Rac、CDC42)和血小板的GEF进一步研究蛋白酶激活的受体(PAR1和PAR4)在血小板形状变化中的作用。

DESCRIPTION (provided by applicant): The long-term goals of this research program are to increase our basic knowledge of how plasma proteins interact with circulating blood platelets leading to their activation and shape change at the site of vascular injury. These reactions play a significant role in cardiovascular disease leading to heart attack and stroke in humans. The approach includes an investigation of the signaling process initiated on the surface of the platelet by thrombin and von Willebrand factor (VWF) and their relationship to the proteins of the cytoskeleton that control the shape of the platelets. These studies will focus on the glycoprotein Ib-lX-V complex, its binding to the a, b, and g filamins in the platelets, and the relationship of the filamins to a guanine nucleotide exchange factor (GEF) with DH-PH domains. This GEF called filamin associated protein has been characterized in our laboratory. These studies will then be extended to the specific small GTPases such as Rho, Rac, and Cdc42 that function as substrates for the GEFs and play a specific role in the development of filopodia, lamellipodia, stress fibers and focal adhesions when platelets are activated. In parallel experiments, the protease-activated receptors (PAR1 and PAR4) will be further examined for their role in platelet shape change via the small GTPases (Rho, Rac, Cdc42) and the platelet GEFs.