PI3K/lnRPT/SMAD3信号轴调控炎症反应诱发肺动脉高压的机制研究

肺动脉高压(PAH)发病机制复杂，死亡率高，肺血管重构是其重要的病理学基础，炎症反应是肺血管重构的诱因之一，可诱发肺动脉平滑肌细胞(PASMC)异常增殖、迁移及细胞基质合成等过程。lncRNA是一类具有生物学功能的非编码RNA，前期研究发现一个受PIK3下调的lncRNA lnRPT可抑制PASMC增殖，且在PAH大鼠肺动脉显著下调；lnRPT可调控SMAD3等炎症相关转录因子的作用。推测，PI3K/lnRPT/SMAD3信号轴可诱发炎症反应参与诱发PAH。本项目拟从分子水平全面揭示lnRPT的表达、调控、功能和作用机制;以低氧或MCT诱导的PAH大鼠及lnPRT基因敲除大鼠为模型，探讨lnRPT在炎症反应、血管重构和PAH发生中的作用;明确lnRPT表达与PAH发生的临床相关性。研究将从lncRNA角度阐述炎症反应诱发PAH的新机制，为开发基于抑制炎症反应的治疗药物提供新思路。

Pulmonary arterial hypertension (PAH), a complex vascular disease with a dreadful survival rate, is characterized by progressive structural remodeling of pulmonary arteries. Inflammation is a trigger in this process, which could induce abnormal matrix synthesis, proliferation and migration of pulmonary arterial smooth muscle cell (PASMC). Long non-coding RNAs (lncRNA) are a novel regulator with multiple biological functions, however, little is known about their role and mechanism in the development of PAH. In preliminary study, a lncRNA lnRPT was identified to be down-regulated via PI3K activation and repress PASMC proliferation. Moreover, LnRPT was down-regulated in the arteries of PAH rats and regulated the activity of SMAD3 and other transcription factors associated with inflammation. Based on the results above, we propose that PI3K/LnRPT/SMAD3 axis might contribute to the development of PAH via modulating inflammation. In this proposal, we will study expression regulation of lnRPT and investigate its biological function and possible mechanism related to inflammation. Using hypoxia or MCT induced PAH rat model and lnRPT knockout rat, the impact of lnRPT on inflammation, vascular remodeling and PAH development will be investigated. Finally, the clinical relationship between lnRPT level and PAH development will be evaluated. The main purpose of this project is to elucidate a new molecular mechanism of inflammation-induced PAH involved in lncRNA. The results will also provide a new clue to develop drug for PAH based on inhibition of inflammation.