自噬-凋亡在低氧性肺动脉高压自然逆转中的作用及分子机制研究

项目名称： 自噬-凋亡在低氧性肺动脉高压自然逆转中的作用及分子机制研究

项目编号： No.81471816

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： 李志超

作者单位： 中国人民解放军第四军医大学

项目金额： 73万元

中文摘要： 以肺血管收缩和肺血管重建为特征的低氧性肺动脉高压（HPH）的确切机制尚不清楚，曾认为HPH时发生的肺血管重建是难以恢复的，最近研究证明纠正低氧后增厚的肺小血管壁和增高的肺动脉压是可以逆转的，但其分子机制所知甚少。我们认为在低氧期肺动脉平滑肌细胞（PASMCs）发生的自噬是导致复氧后HPH自然逆转的基础，发生自噬尤其是过度自噬的细胞在复氧后不能迅速再适应, 从而导致ROS生成改变加速细胞凋亡，促使HPH的逆转。鉴于AMPK和mTOR对细胞增殖、能量代谢等方面有重要调节功能，结合我们前期已经证明Skp2通过调节P27进而促进PASMCs增殖和抑制凋亡中的重要作用，本项目拟从动物和细胞水平动态观察复氧后肺血管重建和PASMCs自噬、凋亡的动态变化，并从ROS/AMPK/mTOR/Skp2入手探讨HPH自然逆转的分子机制，从新的视角研究HPH的发生发展机制，为防治HPH提供新的线索和思路。

中文关键词： 肺动脉高压；慢性高原病；凋亡；自噬；氧化应激

英文摘要： Exact mechanism of hypoxic pulmonary hypertension (HPH) characterized by pulmonary vasoconstriction and pulmonary vascular remodeling is not clear. It should have considered that happened pulmonary artery remodeling in HPH is difficult to restore, and the latest studies show that is a misunderstanding. The thickened pulmonary vascular wall and increased pulmonary arterial pressure can be reversed after recover oxygen. However, the molecular mechanisms of reversing pulmonary vascular remodeling were known very little. We hypothesis that pulmonary artery smooth muscle cells (PASMCs) happened autophagy in low oxygen is the basis of HPH natural reversed. The cell happed autophagy，especially excess autophgy must not be rehabilitation immediately after recovery oxygen, which changes in ROS generation and accelerates cellular apoptosis, so promotes the reversal of HPH. Given the effects of AMPK and mTOR on cell proliferation, and energy metabolism, and our earlier experimental results that Skp2 plays an important role through regulating P27 to facilitate proliferation and inhibit apoptosis of PASMCs,the project intends to observe the dynamic changes of pulmonary vascular remodeling and PASMCs autophagy and apoptosis, and the role of ROS/AMPK/mTOR /Skp2 in HPH natural reversed from animal and cell level. The project would provide new clues and ideas from new perspective for underlying mechanism and control HPH.

英文关键词： pulmonary hypertension;chronic altitude disease;apoptosis;autophagy;oxidative stress