PTPN22在血小板整合素aIIbb3信号转导和血栓形成中的作用机制研究

蛋白酪氨酸磷酸酶PTPN22通过去磷酸化蛋白激酶调节细胞信号转导。血小板整合素aIIbb3信号转导受多种蛋白激酶调控。我们前期发现人和小鼠血小板均表达PTPN22，但其在血小板aIIbb3信号转导及血栓形成中的作用未知。通过抑制PTPN22，我们发现胶原和凝血酶诱导的血小板聚集显著增加。此外，血小板的铺展能力和血块收缩能力（aIIbb3信号转导标志性事件）也显著增强，提示PTPN22参与调控血小板aIIbb3信号转导，但具体分子机制未知，也未见相关报道。为此，本课题拟在前期基础上，利用PTPN22敲基因和转基因小鼠，通过体外实验研究PTPN22在aIIbb3信号转导中的作用及分子机制，体内动物模型研究PTPN22在血小板参与体内止血和血栓中的作用。从而阐明PTPN22对血小板aIIbb3信号转导的调控机制，加深对血小板功能调控的理解，进而为血小板功能异常相关疾病的治疗提供新靶点和新思路。

Protein tyrosine phosphatase PTPN22 regulates cellular signaling transduction through de-phosphorylation of protein kinases. Platelet integrin aIIbb3 signaling is regulated by several protein kinases. We previously found PTPN22 expression in both human and mouse platelets, but its role in platelet aIIbb3 signaling transduction and thrombus formation remains unclear. Through inhibition of PTPN22, we further found that collagen- or thrombin-mediated platelet aggregation was significantly increased. In addition, platelet spreading and clot retraction (regulated by aIIbb3 signaling) was also significantly enhanced, indicating PTPN22 might be involved in the regulation of platelet aIIbb3 signaling transduction. However, the exact molecular mechanism is unknown without relevant reports. Based on the information mentioned above, this project aims to investigate the role and molecular mechanism of PTPN22 in platelet aIIbb3 signaling transduction in vitro, hemostasis and arterial thrombus formation in vivo using PTPN22 knockout and transgenic mouse to uncover the mechanism by how PTPN22 regulates aIIbb3 signaling transduction, which might enhance the understanding of the regulation of platelet function in order to provide new target or theory for treating disorders associated with abnormal platelet function.