Proteins of Blood Coagulation

描述（由申请人提供）：本研究项目的长期目标是增加我们关于血浆蛋白如何与循环血小板相互作用导致其在血管损伤部位激活和形状改变的基本知识。这些反应在导致人类心脏病发作和中风的心血管疾病中起着重要作用。该方法包括对凝血酶和血管性血友病因子（VWF）在血小板表面启动的信号传导过程的研究，以及它们与控制血小板形状的细胞骨架蛋白的关系。这些研究将集中于糖蛋白Ib-lX-V复合物，其与血小板中a、b和g丝蛋白的结合，以及丝蛋白与具有DH-PH结构域的鸟嘌呤核苷酸交换因子（GEF）的关系。这种被称为丝素相关蛋白的GEF已经在我们的实验室中进行了表征。这些研究随后将扩展到特定的小gtp酶，如Rho、Rac和Cdc42，它们作为gef的底物，在血小板被激活时丝状足、板足、应力纤维和局灶粘连的发展中发挥特定作用。在平行实验中，蛋白酶激活受体（PAR1和PAR4）将通过小gtp酶（Rho, Rac, Cdc42）和血小板gef进一步研究它们在血小板形状改变中的作用。

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.