肺动脉高压发病率和死亡率高，其主要病理特征为肺动脉重构，但机制不完全清楚，缺乏确切有效的防治药物。申请人前期研究发现低氧性肺动脉高压（HPH）的发病与肺组织中p53表达水平降低有关，但慢性低氧时p53信号通路调控异常的分子机制及其在HPH疾病发生发展中的作用尚不清楚。本研究将应用p53等多种转基因小鼠模型、细胞分子生物学及病理生理学技术，详细阐明在慢性低氧状态下：1）p53在肺动脉平滑肌细胞（PASMC）、内皮细胞（PAEC）和成纤维细胞（PAF）中的分布变化；2）低氧诱导因子-1α（HIF-1α）、p19ARF、鼠双微体（MDM2）、肺抵抗蛋白（LRP）、组成型光形态发生（Cop）1蛋白对p53的调节作用；3）在HPH发病过程中，p53表达异常对PASMC、PAEC和PAF细胞增殖、凋亡和功能的影响。

Pulmonary hypertension (PH) is a disease with high morbidity and mortality. The major pathological feature of PH is pulmonary arterial remodeling, but the mechanism under this still remain unknown. According to our previous research, we found down-regulated P53 expression contributes greatly to PH. However, how P53 regulate the proliferation of remains unclear. In this study, by using transgenic mice, cell molecular biology and pathophysiological technology, we aim to detect:1)the distribution of P53 in PASMC、PAEC and PAF;2) how HIF-1α、p19ARF and LRP regulate the expression and activity of P53;3)the effect of P53 on the proliferation and apoptosis of PASMCs、PAEC and PAF.