miR-182-3p新靶标MYADM在肺动脉高压血管重构中的作用与分子机制研究

肺动脉高压（Pulmonary Arterial Hypertension, PAH）是以血管重构为主要病理基础的罕见病，机制不明、缺乏有效预警信号和治疗靶点。申请人首次发现表观调控分子miR-182-3p及其新靶标MYADM对血管重构的调控作用，在PAH大鼠中miR-182-3p/MYADM表达显著改变，提示MYADM对PAH血管重构的潜在作用，具有重要研究前景。拟申请本课题，结合蛋白质组学技术、PCR芯片技术及CRISPRs/Cas9基因修饰技术等新技术与新方法，在分子、细胞，特别是申请人前期建立的MYADM基因敲除大鼠水平，揭示PAH血管重构中miR-182-3p/MYADM的表达规律与调控作用，探索MYADM下游调控基因及其信号传导通路，从而阐明miR-182-3p新靶标MYADM在肺动脉高压血管重构中的作用与分子机制，为PAH早期预警信号探索、靶点研究和药物研发提供重要依据。

Pulmonary arterial hypertension (PAH), a challenge to modern medicine, is a disease of the small pulmonary arteries (PAs), characterized by vascular remodeling leading to an increase in PA pressure and a progressive increase in pulmonary vascular resistance. Although progress has been made over the past decade, the cellular and molecular mechanisms for PH are still unclear. For the first time, we found that miR-182-3p is a new modulator of vascular remodeling via its new target Myeloid-associated differentiation marker (MYADM). What’s more, the expression profiles of miR-182-3p/MYADM in PAH rats are significantly changed, which indicates its role of regulating in PAH vascular remodeling. On the basis of previous observations, we propose a critical role for miR-182-3p new target MYADM in the development of PAH vascular remodeling. A proteome profiler of Isobaric tag for relative and absolute quantitation(iTRAQ) and gene profiler of PCR array and CRISPRs/Cas9 based gene knockout rats will be used in this project to profile the miR-182-3p/MYADM expression in rat pulmonary artery (PA) of hypoxic rats, to examine the role of microRNA-182-3p/MYADM in hypoxic PAH and to find the molecular mechanism of the regulation of miR-182-3p/MYADM on PAH vascular remodeling. This study belongs to the original and innovative research. The results will provide support for the study and exploration of the PAH early warning signals and target. It will benefit to the new drug research and development of PAH.