Cortactin在紫绀型先心病内源性肺保护中的作用及机制研究

紫绀型先心病慢性缺氧，机体代偿性改变，术前肺功能无明显受损；但体外循环心脏术后肺缺血再灌注损伤(LIRI)严重。.我们前期组学研究发现，慢性缺氧小鼠肺组织皮层肌动蛋白结合蛋白(cortactin)上调，但随后LIRI期表达降低，并伴caveolin-1水平上升；结合文献，我们推测cortactin是内源性肺保护因子，LIRI期间caveolin-1抑制cortactin表达引起肺损伤。.本课题将以siRNA和基因转移技术①研究cortactin对人肺微血管内皮细胞骨架蛋白和通透性的影响，明确cortactin内源性肺保护作用②证实caveolin-1对cortactin表达的调节作用，Rac1是其中关键环节③研究调控caveolin-1-Rac1-cortactin途径能否减轻LIRI。本课题旨在阐明通过Rac1激活内源性保护因子cortatin是紫绀型先心病术后LIRI新的潜在治疗靶点。

To maintain a relatively normal lung function under preoperative chronic hypoxia condition, the body of cyanotic congenital heart disease (CHD) patient may undergo a series of compensatory changes. Heart surgery under cardiopulmonary bypass (CPB) is preferred treatment of cyanotic CHD. However, the postoperative lung ischemia reperfusion injury (LIRI) is severe and inevitable. . We previously found that cortactin was up-regulated in the lung of cyanotic mice, while in the subsequent LIRI process its expression decreased with its upstream regulatory protein caveolin-1 expression increasing. Therefore, we hypothesize that decreased cortactin due to up-regulation of caveolin-1 during CPB related LIRI may induce lung injury.. In this project, we will construct cortactin and caveolin-1 gene silencing and overexpression human pulmonary microvascular endothelial cells (HPMVECs) model via siRNA and gene transfer techniques, as well as chronic hypoxic model of mice. First, we will make it explicit the endogenous pulmonary protective role of cortactin in cyanotic CHD. Second, we will clarify the possible underlying mechanism of cortactin down-regulation induced lung injury and the key role of Rac1 during LIRI period. Third, we will explore whether the regulation of caveolin-1-Rac-1-cortactin pathway could promote the continuous overexpression of cortactin and therefore alleviate LIRI after cyanosis in the ischemia reperfusion model of chronic hypoxia mice. Our research will provide a new therapeutic strategy for the prevention and treatment of LIRI for cyanotic CHD.