CircRNA_017665作为miR-182-3p分子海绵介导肺动脉高压血管重构的机制研究

肺动脉高压(PAH)是以肺血管重构为主要病变的恶性罕见病，早期难识别，机制与治疗靶点均不明确。表观遗传调控，特别是环状RNA(circRNA)竞争性结合miRNA的分子海绵作用在肺血管重构中发挥了关键作用。申请人前期原创性研究首次发现miR-182-3p通过靶向Myadm调控PAH血管重构,近期发现circRNA_017665靶向结合miR-182-3p，可能是miR-182-3p分子海绵，参与PAH肺血管重构形成。本项目拟在分子、细胞、模式动物及临床患者水平，进一步考察circRNA_017665/miR-182-3p在PAH中的表达规律，探索其作为生物标志物的可能性，阐明circRNA_017665作为miR-182-3p分子海绵调控血管重构、介导PAH形成的详细机制。本项目的成功实施将为明确PAH血管重构的调控机制及早期分子标志识别提供重要佐证，有望为PAH的诊断和治疗提供新的策略。

Pulmonary Arterial Hypertension (PAH) is a lethal disease correlating with vascular remodeling. Circular RNAs are a new class of non-coding single-stranded RNAs, characterized by covalently closed loop structures without a free 3’ PolyA tails or 5’ caps compared with linear RNAs, which makes it different from long-noncoding RNA and microRNA(miRNA). CircRNAs are the competitive endogenous RNAs (ceRNAs) by binding to miRNA through miRNA response elements (MREs) (i.e “miRNA sponge”), thereby reducing the quantity of miRNA available to target mRNA, subsequently promoting mRNA stability or protein expression, indicating the potential role of circRNAs on the initiation and progress of human diseases. .Results from our previous study showed that mir-182-3p regulated PAH vascular remodeling through targeting Myadm, which was recognized by the academic community. Recent studies have shown that during PAH formation, the expression level of circRNA_017665 is abnormally elevated, and its targeted binding to mir-182-3p is a molecular sponge of mir-182-3p. We apply for this project, at the molecular, cellular, animal models and clinical patients with PAH levels in circRNA_017665 as miR-182-3p molecular sponge, adjust the PAH vascular remodeling plasma marker research, the molecular mechanism of formation and the results will help to clarify regulatory mechanism of PAH vascular remodeling and the early molecular marker to identify, for the early diagnosis and intervention, reverse vascular reconstruction, to improve the long-term survival rate has a positive effect, PAH patients to create independent intellectual property rights of new drugs in our country, improve drug accessibility, reduce the burden of disease patients, is of great significance.