Akt-mTOR-Snail信号通路诱导肺动脉高压内皮细胞向间充质细胞转化的分子机理研究

项目名称： Akt-mTOR-Snail信号通路诱导肺动脉高压内皮细胞向间充质细胞转化的分子机理研究

项目编号： No.81470249

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 李圣青

作者单位： 复旦大学

项目金额： 75万元

中文摘要： 肺动脉高压的肺血管重构是临床治疗的难点，肺血管内皮细胞向间充质细胞的转化(EnMT)是肺血管重构的重要病理过程。我们前期研究发现mTOR抑制剂可显著抑制EnMT；mTORC1可与转录因子Snail（Snail与EnMT密切相关）结合；Akt抑制剂在抑制mTOR磷酸化同时可降低Snail的表达，提示mTOR与Snail蛋白稳定性相关。体外激酶研究发现mTOR可磷酸化Snail，提示Snial为mTOR分子的下游。综上，我们发现Akt-mTOR-Snail通路与EnMT密切相关。本课题着重阐明Akt-mTOR-Snail信号通路诱导EnMT的分子机理，包括mTOR对Snail的磷酸化调控和Snail靶基因的研究；采用小鼠肺动脉高压模型验证mTOR抑制剂对EnMT的抑制作用；观察Akt-mTOR-Snail信号通路分子表达变化对患者预后的影响，为mTOR抑制剂用于临床治疗提供理论依据。

中文关键词： 肺动脉高压；肺血管重构；肺动脉内皮细胞；信号通路；雷帕霉素哺乳动物细胞靶蛋白

英文摘要： The treatment of pulmonary vascular remodeling in pulmonary hypertension (PH) is a difficult clinical problem, and pulmonary vascular endothelial-mesenchymal transition (EnMT) is an important pathological process of pulmonary vascular remodeling. Our previous study found that mTOR inhibitors can significantly inhibit EnMT; mTORC1 can be combined with the transcription factor Snail, which is closely related to the process of EnMT; Akt inhibitors can inhibit mTOR phosphorylation while reducing the expression level of Snail, suggesting that mTOR is associated with Snail protein stability. Further study found that mTOR kinase can phosphorylate Snail protein in vitro kinase assay, suggesting that Snial is the downstream of mTOR kinase. In summary, we found that Akt-mTOR-Snail signaling pathway is closely related to EnMT. in order to provide a theoretical basis for mTOR inhibitors in the clinical treatment of PH,this project is going to focus on elucidating the molecular mechanism of Akt-mTOR-Snail signaling pathway induced EnMT, including the study of phosphorylation regulation of mTOR on Snail protein and the preliminary studies of Snail target genes; the validation of mTOR inhibitors for the treatment of EnMT in the pulmonary hypertension mice model; the observation of the effect of Akt-mTOR-Snail signaling pathway molecules expression levels on the prognosis of PH patients.

英文关键词： Pulmonary Hypertension;Pulmonary Vascular Remodeling;Pulmonary Arterial Endothelial;Signal Pathway;mTOR