肺动脉高压是一种渐进性的致命疾病，可导致右心衰竭而死亡。由于对闭塞性血管重塑的机制了解不足，目前的治疗方法只轻微改善病人的生活质量。主要障碍之一是缺乏适当的自发小鼠肺动脉高压模型来描述肺动脉高压患者的病理生理变化。p97/IP3R3/PTEN信号通路可以调节癌细胞蛋白质方面的质量控制，调节泛素化过程进而控制细胞增殖。前期研究结果表明PTEN/AKT/HIF信号通路在肺动脉高压血管重塑过程中发挥着至关重要的作用。因此本项目致力于建立p97转基因小鼠自发的肺动脉高压动物模型。该模型通过动物实验和细胞实验验证肺动脉高压疾病的各种病理表型，并和人类肺动脉高压患者临床表型做比较，评价其构建效果。结合基因敲除和转基因小鼠模型、分子生物学实验及离体肺循环实验揭示p97/PTEN/HIF信号轴通路在肺动脉高压疾病中的作用及调控机制。为研究人类肺动脉高压的发生、发展及其复杂的机制奠定了新的模型基础。

Pulmonary arterial hypertension is a progressive fatal disease that can lead to right heart failure and death. The understanding mechanism of occlusive vascular remodeling, current treatments only slightly improve the patient's quality of life.One of the main obstacles is the lack of an appropriate spontaneous mouse model of pulmonary hypertension to describe pathophysiological changes in patients with severe pulmonary hypertension. P97/IP3R3/PTEN signaling pathway can regulate the protein quality control of cancer, regulate the ubiquitination and control cell proliferation. Previous studies have shown that the PTEN/AKT/HIF signaling pathway plays a crucial role in the remodeling of pulmonary hypertension vessels. Therefore, the project focuses on the establishment of spontaneous pulmonary hypertension animal model in p97 transgenic mice. The model verifies various pathological phenotypes of pulmonary hypertension disease through animal experiments and cell experiments. The model was evaluated through being compared with the clinical phenotypes of patients with pulmonary hypertension. Gene knockout and transgenic mice models, molecular biological experiments and in vitro pulmonary circulation experiments revealed the role and regulatory mechanism of p97 / PTEN / HIF signaling axis pathway in pulmonary hypertension.This model provides a new model basis for the study of the occurrence, development and complex mechanism of pulmonary hypertension in humans.