环状RNA mmu_circ_0001033调节低氧性肺动脉高压的机制研究

Recent studies suggest that circular RNA (circRNA) may play an important role in the occurrence of hypoxic pulmonary hypertension (HPH). Our previous studies showed that the target circRNA (mmu_circ_0001033) was abnormal expressed in mice models of HPH and pulmonary artery smooth muscle cells (PASMC), and its overexpression inhibited the proliferation of hypoxia PASMC and prevented HPH occurrence. According to these studies, this project proposes that there is a new mechanism for the regulation of circular RNA in HPH.We will observe the changes of HPH syndromes in mice models and cellular changes such as cell proliferation in cell models to clear the function of circRNA in PHP by using the overexpression of the target circRNA in lentivirus vector. Experimental methods such as RIP and luciferase reporter gene experiment etc will be used to clarify the expression and regulation of miRNAs and downstream mRNAs of the miRNAs adsorbed by the target circRNA, and to determine the regulatory relationships among circRNA, miRNA and mRNA, and further clarify the new mechanism of miRNA sponge of circRNA regulating HPH. Lung tissue and blood samples from patients with pulmonary hypertension will be obtained to test the function of the target circRNA in order to find HPH biomarker. This project aims to clarify a new mechanism of HPH regulated by circRNA and to provide a novel strategy for preventing and treating HPH.

新近研究提示：环状RNA（circRNA）可能在低氧性肺动脉高压（HPH）发生中有重要作用。我们前期发现：mmu_circ_0001033（目的circRNA）在HPH小鼠肺和肺动脉平滑肌细胞（PASMC）中异常表达，其过表达抑制低氧性PASMC增殖和预防HPH 发生。本项目据此提出：HPH中存在环状RNA调控新机制。拟对HPH小鼠和细胞模型进行目的circRNA过表达慢病毒转染，观察HPH特征及细胞增殖等变化，明确circRNA调节HPH新功能；采用RIP和荧光素酶报告基因实验等探明目的circRNA吸附的miRNA及其下游靶基因表达与调控，弄清circRNA、miRNA与mRNA之间调控关系，深度阐明circRNA调节HPH的miRNA海绵机制；取肺动脉高压患者肺组织和血标本验证目标circRNA，确立HPH生物标志物。阐明circRNA调节HPH新机制，为确立防治新策略提供研究基础。

低氧性肺动脉高压（HPH）对人的长期严重危害依然未得到很好解决，是治疗极为棘手、高致死率和高致残率的病理生理综合征。早诊早治HPH显得尤其重要，而关键在于阐明HPH发生机制，HPH发生机制至今尚未完全阐明。本项目构建低氧性肺动脉高压（HPH）小鼠和细胞模型，进行环状RNA mmu_circ_0001033过表达慢病毒转染，观察HPH特征及细胞增殖、迁移和凋亡等变化，用RIP和荧光素酶报告基因实验等探讨circRNA吸附的miRNA及其下游靶基因表达与调控，试图阐明circRNA调节HPH的机制，并取肺动脉高压患者的临床标本进行验证。结果发现，mmu_circ_0001033具有调节HPH的新功能，mmu_circ_0001033通过miRNA海绵新机制调节HPH发生，初步阐明mmu_circ_0001033吸附的miRNA的靶基因及其信号通路调控机制。为确立HPH新的circRNA诊断标志物和防治靶标提供科学依据，具有潜在的临床应用价值。研究结果在 SCI 收录期刊和中国科技核心期刊(中国科技论文统计源期刊）上发表论文共 15篇， 其中 SCI 收录 9篇，中文论文6篇，都标注有“国家自然科学基金资助（编号：81870044）”。