靶向低氧反应相关的信号通路联合治疗肺动脉高压的作用及机制研究

肺动脉高压（Pulmonary Arterial Hypertension，PAH）是以肺血管持续性收缩、肺血管重构为主要病理特征的进行性致命疾病，目前尚无药物可以治愈。低氧反应相关的HIF依赖信号通路（PHD2、VHL、HIF等）和非依赖信号通路（mTOR、UPR、UCHL1等）在PH发生发展中起着关键作用，但是它们之间的交叉调控目前还不完全清楚。我们前期对HIF和mTOR信号通路在PH中的作用进行了大量研究，发现平滑肌细胞HIF1α或内皮细胞HIF2α缺失可缓解低氧诱导的肺动脉高压；mTOR形成的两种复合物mTORC1和mTORC2在PH发病过程发挥了不同作用；抑制mTORC1缓解PH发展，而抑制mTORC2促进PH发展。本项目拟通过细胞实验和动物实验，进一步探究低氧反应相关信号通路中关键分子在PH发生发展中的作用及交叉调控机制，靶向联合用药，以期建立一种治疗肺动脉高压的有效策略。

Pulmonary arterial hypertension (PAH) is a rare but progressive and deadly disease that mainly affects the pulmonary vasculature and the right ventricle. Two kinds of O2-sensing pathways which promote hypoxia response by regulating transcription and mRNA translation consists of hypoxia-inducible factor α (HIFα) signaling pathway, and HIFa-independent pathways which including the unfolded protein response (UPR), a complex containing the mammalian target of rapamycin (mTOR) kinase, and Ubiquitin C-Terminal Hydrolase L1(UCHL1). Our previous studies demonstrated both HIF and mTOR play critical roles in the development of pulmonary hypertension. Deletion of HIF1a in smooth muscle cells or HIF2a in endothelial cells attenuated the development of pulmonary hypertension. Using a series of transgenic mice strains, we identified a differential role of mTOR complex 1 and complex 2, two functionally distinct mTOR complexes, in the development of pulmonary hypertension (PH). Inhibition of mTORC1 attenuated the development of PH; however, inhibition of mTORC2 caused spontaneous PH, potentially due to up-regulation of platelet-derived growth factor receptors (PDGFR) in pulmonary arterial smooth muscle cells (PASMC), and compromised the therapeutic effect of the mTOR inhibitors on PH. Here, we propose therefore to investigate the crosstalk between hypoxia sensitive pathways. We propose to describe a promising therapeutic strategy using combination treatment with the mTOR inhibitors, PDGFR inhibitors, and UCHL1 inhibitors on PH and right ventricular hypertrophy. The data from this study will provide an important mechanism-based perspective for developing novel therapies for patients with pulmonary arterial hypertension and right heart failure.