ADAM17介导血小板受体GPIba 胞外段水解在免疫性血小板减少症中的作用机制研究

免疫性血小板减少症（ITP）是以血小板破坏为主要特征的免疫相关性疾病，但其机制尚未完全阐明，故其治疗策略局限。深入探索ITP中血小板破坏的机制，可拓宽对ITP发病机制的认识，为其治疗提供新靶点和策略。金属蛋白酶ADAM17通过水解血小板GPIb-IX-V中GPIba胞外段参与血小板破坏。ITP患者GPIba胞外段水解增加，提示其参与ITP发病。本课题组发现GPIb-IX-V与NADPH氧化酶（Nox）相互作用，Nox是活性氧（ROS）的主要来源，而ROS调节ADAM17活化。但GPIb-IX-V/Nox/ROS是否通过ADAM17参与ITP中GPIba胞外段水解未见报道。本项目拟用临床样本分析GPIba胞外段水解与ITP相关性、体外实验及ITP动物模型研究GPIb-IX-V/Nox/ROS是否参与GPIba胞外段水解，明确其在ITP血小板破坏中的作用。如期完成，可为ITP的治疗提供新思路。

Immune thrombocytopenia (ITP) is an immune-related disease characterized by accelerated platelet destruction. However, the mechanism underlying this disease is not very clear, leading to the limitation on its treatment.Thus, investigating the molecular mechanism of platelet destruction in ITP would enhance our understanding on the pathogenesis of ITP and provide a new target and strategy for the treatment. ADAM17-mediated ectodomain shedding of platelet receptor GPIba (a subunit of GPIb-IX-V) has been reported to be involved in platelet destruction. Increased ectodomain shedding of GPIba was observed in ITP, suggesting its involvement in the pathogenesis of ITP. In a previous study, we demonstrated that GPIb-IX-V binds to TRAF4 (TNF receptor associated factor 4) and TRAF4 binds to p47phox, a subunit of NADPH oxidase (Nox), the origin of ROS production, which regulates ADAM17 activation. Whether GPIb-IX-V/Nox/ROS is involved in the ectodomain shedding of GPIba via ADAM17 activation in ITP has not been reported previously. In this study, we propose to analyse the association of GPIba ectodomain shedding with ITP through clinical samples and investigate whether GPIb-IX-V/Nox/ROS is involved in the ectodomain shedding of GPIba in ITP through in vitro and in vivo (ITP mouse model) experiments, illuminating its role in the platelet destruction in ITP. If accomplished on schedule, this study could provide a new strategy for ITP treatment.