LncRNA RP11-400N13在低氧诱发肺血管重构过程中依赖雌激素受体α介导的调控作用及机制

肺血管重构是导致低氧性肺动脉高压(PH)不可逆改变的重要因素，但机制仍未完全阐明。最近研究证实，长链非编码RNA（LncRNA）参与低氧PH肺血管重构。我们在低氧肺动脉平滑肌细胞(PASMC)中筛选出差异高表达的LncRNA RP11-400N13，前期预实验结果显示：它可以激活雌激素受体α（ERα），可能分别通过内质网应激（ERS）和转录因子KLF5调控PASMC增殖、凋亡、迁移等生物学功能。申请者前两个基金课题研究证实，低氧激活的ERS和KLF5参与低氧肺血管重构。本课题将构建LncRNA RP11-400N13基因敲除动物模型，通过慢病毒相关载体，RNA干扰等实验手段，从分子、细胞以及动物等多个水平探讨LncRNA RP11-400N13是否通过ERα介导调节ERS和KLF5，参与PASMC增殖、凋亡、迁移等生物活性调控及其深入机制，旨在为PH寻找有效临床治疗靶点开辟新的窗口。

Pulmonary vascular remodeling is an important factor leading to the irreversible hypoxic pulmonary hypertension (PH), but the underlying mechanism has not been fully elucidated. Emerging studies have confirmed that LncRNA is involved in pulmonary vascular remodeling of PH. Recently, we screened out the LncRNA RP11-400N13 with significantly higher expression in pulmonary artery smooth muscle cells (PASMC) when exposed to hypoxia. Our preliminary experimental results showed that LncRNA RP11-400N13 could activate the estrogen receptor alpha (ERα), and might regulate the proliferation, apoptosis, migration and other biological functions of PASMC through endoplasmic reticulum stress (ERS) and transcription factor KLF5. The applicant's two of previous funded studies confirmed that hypoxic-activated ERS and KLF5 are involved in hypoxic pulmonary vascular remodeling. We will build an LncRNA RP11-400N13 gene knockout animal models, with lentiviral vector, RNA interference, and other experimental techniques. This study aims to explore the influence of LncRNA RP11-400N13 on PASMC proliferation, apoptosis and migration mediated by ERα-ERS and ERα-KLF5 pathways, and its underlying regulating mechanism from the molecular, cellular, and animal levels. We expected to open a new window for finding effective clinical therapeutic targets for PH.