Zyxin对血小板生成和GPIb-IX复合物膜表面表达的调控作用及机制研究

血小板由巨核细胞产生，其过程受巨核细胞骨架系统的精准调控。Zyxin是一种黏着斑蛋白，在调控细胞肌动蛋白骨架重组中发挥重要作用。Zyxin在血小板高表达，但其在血小板产生中的作用尚未知。申请者初步研究发现，与野生型小鼠相比，zyxin敲除小鼠血小板数量减少三分之二，体积增大近一倍，呈巨血小板减少症表型，而且血小板和巨核细胞膜糖蛋白（glycoprotein, GP）Ib-IX表面表达明显减低，提示zyxin在调节血小板生成和GPIb-IX表面表达中可能起关键作用。本项目将首先研究确定zyxin对二者的调控作用，进而通过研究zyxin对巨核细胞和血小板骨架系统的调控作用阐明机制，最后在人巨核细胞中进行验证。巨血小板减少症是一类异质性出血疾病，由于多数机制不明，给其诊治带来困难。本课题不但揭示血小板产生和GPIb-IX表面表达的调控机制，更为揭示巨血小板减少症的发生机制及其精准诊疗奠定基础。

Platelets are produced from megakaryocytes under the regulation of cytoskeleton reorganization. Zyxin, a focal adhesion protein, plays important roles in regulating actin cytoskeleton reorganization. Zyxin is highly expressed in platelets; however, the role of zyxin in thrombopoiesis is unclear. In our preliminary studies, we found that zyxin-deficient mice displayed macrothrombocytopenia, with two thirds reduction of platelet count and almost one fold increase of platelet size, and showed significantly reduced surface expression of glycoprotein (GP) Ib-IX complex on platelets and megakaryocytes, suggesting the critical role of zyxin in platelet biogenesis and GPIb-IX surface expression. This study will first investigate the role of zyxin in platelet biogenesis and GPIb-IX surface expression, then elucidate the mechanism by studying the regulatory effect of zyxin on the cytoskeleton of megakaryocytes and platelets, and lastly verify the regulatory role of zyxin in human megakaryocytes. Macrothrombocytopenia is a heterogeneous bleeding disorder, which is difficult to diagnose and treat because the pathogenesis has not been completely understood. This study will not only reveal the mechanism of platelet biogenesis and GPIb-IX surface expression, but also lay the foundation for revealing the pathogenesis of macrothrombocytopenia and its precise diagnosis and therapy.