蛋白酪氨酸磷酸酶SHP2调节血管内皮屏障通透性的生理意义及分子机制研究

项目名称： 蛋白酪氨酸磷酸酶SHP2调节血管内皮屏障通透性的生理意义及分子机制研究

项目编号： No.31471258

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 程洪强

作者单位： 浙江大学

项目金额： 80万元

中文摘要： 血管内皮细胞形成一个动态变化，选择性通透的屏障系统，其与组织液的稳态，炎症的发生发展以及血管的新生与重构过程紧密相关。血管内皮损伤会引发血管通透性升高，直接导致出血及炎症反应，甚至是脓毒症。粘连分子VE-Cadherin与多种Catenins蛋白形成的复合物蛋白翻译后磷酸化修饰是一种重要的调控内皮屏障功能的手段。SHP2是一个普遍表达的胞内非受体型蛋白酪氨酸磷酸酶，其参与VE-Cadherin与Catenins复合物的磷酸化修饰的分子过程以及对内皮的屏障功能影响尚不十分清晰。我们前期开展的实验观察到血管内皮特异缺失SHP2导致小鼠胚胎出血和致死。本课题拟结合成年可诱导内皮敲除SHP2小鼠与人脐静脉内皮细胞，揭示SHP2在血管发育，成熟及维持血管内皮屏障稳态中的作用。本项目的成果将为水肿、出血以及炎症的发生提供诊断与治疗的新思路。

中文关键词： SHP2；血管内皮细胞；内皮屏障；磷酸化修饰；细胞连接

英文摘要： The endothelium of vessels forms a dynamic and selective barrier, which is important for interstitial hemeostasis, inflammatory,angiogenesis and vascular remodeling. Injury in endothelium leads to a persistent increase of vascular permeability, inflammatory, leakage and sepsis. Adherens junctions of endothelial cells, comprising of vascular endothelial (VE)-cadherin and associated various catenins, contribute greatly the barrier function. Endothelial barrier is tightly regulated, among which posttranslational protein phosphorylation is important. Protein tyrosine phosphatase SHP2, which is ubiquitously expressed, is reported to be associated with adhesion molecules. However, the role of SHP2 in the vascular permeability in vivo remains elusive. Our priliminary data showed that mice with endothelial cell specific knockout SHP2 are embryonic lethal, which indicates that SHP2 plays a pivotal role in the vascular development and maturation. Therefore, we have three aims. The first is describing phenotypic details of endothelial cell specific SHP2 knockout mice. The embryonic lethality blocks our study about the SHP2 function in adult vasculature, so the second aim is creating adult inducible endothelial specific SHP2 knockout mouse line and study the vascular permeability. For the molecular mechanism, we will utilize HUVEC to in vitro study the effect of impaired SHP2 function on barrier function and adherens molecules expression and phosphorylation modifications. Our research will bring new lights for understanding leakage and clinical therapy.

英文关键词： SHP2;vascular endothelial cells;endothelial barrier;phosphorylation;cell junctions