肺动脉高压（PH）是由于肺血管系统结构和功能的病理性改变，从而导致肺动脉压力和血流阻力进行性增高的致死性疾病。尽管目前对肺动脉高压的诊断和治疗已有一些研究进展，肺动脉高压的发病机制尚未完全清楚​。我们前期研究结果表明PHD2/VHL/HIF1、2α和PI3K/Akt/mTOR信号通路在慢性低氧诱导肺动脉高压的发病过程中发挥着至关重要的作用。本项目计划通过细胞实验及动物实验两个层面，研究信号通路在肺动脉平滑肌细胞增殖、迁移以及表型的转换；内皮细胞损伤、凋亡以及内皮间质细胞转化中的作用机制。结合基因敲除小鼠、肺动脉高压动物模型以及离体肺循环模型实验，研究信号通路中的关键分子在急性低氧引起的肺动脉收缩和慢性低氧诱导肺动脉高压中的作用及调控机制。在此基础上，针对信号通路中的关键蛋白研发靶向药物，评价其在急性低氧肺动脉收缩中的作用以及在慢性低氧肺动脉高压治疗中的意义。

Pulmonary arterial hypertension (PAH) is a progressive, fatal disease characterized by increased pulmonary vascular resistance due to vascular proliferation and remodeling of the pulmonary arterioles that lead to right-sided ventricular failure and, ultimately, death. Although significant advances have been made in the treatment options and management, the mechanism of this disease is still unclear. Our preliminary data shows that PHD2/VHL/HIF1、2αand PI3K/Akt/mTOR signaling pathways play an important role in the pathogenesis of chronic hypoxia-induced pulmonary hypertension. Through both the cell and animal experiments, we aim to study the mechanism of these two signaling pathways in the proliferation, migration and phenotype of pulmonary artery smooth muscle cells, the injury, apoptosis and endothelial-mesenchymal transition of endothelial cell. Combined with knockout mice, pulmonary hypertension animal model and isolated pulmonary circulation model, we will define the different mechanism of the key molecules in these signaling pathways in acute hypoxia-induced hypoxic pulmonary vasoconstriction and chronic hypoxia-induced pulmonary hypertension. based on these research, we will be able to find new drug targeting in the key protein of these signal pathway and make an evaluation of its potential therapeutic effect in the acute hypoxia-induced hypoxic pulmonary vasoconstriction and chronic hypoxia-induced pulmonary hypertension.