AMPK/mTOR 信号通路在肺动脉高压发病中的分子机制及其干预

项目名称： AMPK/mTOR 信号通路在肺动脉高压发病中的分子机制及其干预

项目编号： No.81330002

项目类型： 重点项目

立项/批准年度： 2014

项目学科： 医药、卫生

项目作者： 李满祥

作者单位： 西安交通大学

项目金额： 290万元

中文摘要： 新近的研究提示 AMPK/mTOR 信号通路异常与肺动脉高压的发生相关，但其导致肺血管重塑、诱发肺动脉高压的分子生物学机制尚不清楚。本研究将探讨（1） AMPK 功能受损是否诱发肺血管重塑，导致肺动脉高压；（2）AMPK 是否通过抑制 mTOR 通路，下调 Skp2 表达，抑制泛素蛋白酶系统（UPS）介导的细胞周期抑制蛋白 p21, p27 的降解，抑制肺动脉平滑肌细胞的增殖；（3）AMPK 是否通过抑制 mTOR 功能，下调 MMP2/9 的表达，抑制细胞外间质重塑；（4）激活 AMPK 是否可作为新的治疗靶点，通过调控 mTOR-Skp2/p21/p27-MMP，预防及治疗动物模型中肺动脉高压的发生。本研究将从原代培养的肺动脉平滑肌细胞及低氧、野百合碱诱发的肺动脉高压动物模型两个方面验证我们的假设，并探讨其分子生物学机制，本研究将为肺动脉高压的治疗提供新的理论基础、实验依据、治疗靶点。

中文关键词： 肺动脉高压;AMP；激活蛋白激酶;哺乳类动物雷帕霉素靶蛋白;肺血管重塑;分子机制

英文摘要： Recent study suggests that the abnomal AMPK/mTOR signaling pathway is related to the development of pulmonary artery hypertension, yet its molecular mechanisms leading to the development of pulmonary vascular remodeling are still unclear. In this study we will examine following hypothesis: (1) whehter the impairment of AMPK function leads to vascular remodeling and the development of pulmonary hypertension; (2) whether AMPK inhibits mTOR cascades and further downregulates the expression of Skp2 to inhibit UPS mediated p21/p27 degradation leading to the suppression of proliferation of pulmonary vascular smooth muscle cells; (3) whether AMPK inhibits MMP2/9 production via suppresion of mTOR leading to the inhibition of extracellular matrix remodeling;(4) whether activation of AMPK can serve as a new target to suppress the develoment of pulmonary hypertension in animal model via regulation of mTOR-Skp2/p21/p27-MMP2/9. We will test above hypothesis from primary cultrued pulmonary artery smooth muscle cells and animal model of pulmonary artery hypertension induced by hypoxia and monocrotaline, and further address their molecualr mechanisms. The present study will provide new theretical and expremental evidences and targets to the treatment of pulmonary artery hypertension.

英文关键词： Pulmonary artery hypertension;AMPK ;mTOR;pulmonary vascular remodeling;molecular mechanisms