lncRNAH19/miRNA140信号轴在先天性心脏病合并肺动脉高压中的作用及机制研究

Congenital heart disease (CHD) is a main born defect, with bad prognosis once developing pulmonary arterial hypertension (PAH). The pathogenesis of CHD with PAH (CHD-PAH) is very unclear, and as important regulatory mechanism, lncRNA and miRNA has been the new research orientation in this field. In our previous work, we found two non-coding RNA of lncRNA H19 and miRNA140, closely associated with heart development and remodeling of pulmonary vessels. After further analysis, it showed a high expression of lncRNA H19 in lung tissue and there may be a up and down relationship of lncRNA H19 with miRNA140. In this research, we will explore the function of lncRNA H19 in CHD-PAH by using patients lung tissues, animal model and cell model in aspects of vivo, vitro and molecule, to define the crossing relationship of lncRNA H19 and miRNA140, aiming to figure out the up and down regulatory mechanism of lncRNA H19 and miRNA 140 signal-axis. This research will provide a new thought for molecule mechanism of CHD-PAH, a unique disease in China and a new target for treatment.

先天性心脏病是我国最主要的出生缺陷，一旦罹患肺动脉高压，预后恶劣。先心病合并肺动脉高压（CHD-PAH）的病理机制目前很不清楚，长链非编码RNA(lncRNA)和微小RNA（miRNA）作为重要的表观调控机制，已成为CHD-PAH领域新的研究方向。我们在前期工作中发现两个与心脏发育及肺血管重构紧密相关的非编码RNA--lncRNAH19和miRNA140。进一步分析表明，lncRNAH19在肺组织高表达，并很可能与miRNA140为上下游关系。本研究中，我们将利用患者组织、动物模型和细胞模型，从体内、体外、分子等多个层面研究lncRNAH19在CHD-PAH中的功能，明确lncRNAH19与miRNA140的交互关系，探索lncRNAH19与miRNA140信号轴的上下游调控机制。该研究将为解释先心病合并肺动脉高压这一“中国特色疾病”的分子机制提供新的思路，为治疗提供新的靶点。

在本项目在获得审批后，考虑到前期采集的CHD-PAH患者的肺动脉、肺静脉血清样本的稀缺和珍贵性，决定调整本项目的实验计划，积极开展已采集患者血清样本的转录组（lncRNA、circRNA、microRNA）测序工作，据测序结果，已经发现重度肺动脉高压血清中lncRNA较无PAH的患者中表达较高。后期在新采集的CHD患者血清中进行上述高表达lncRNA的验证工作，目前已完成初步验证，结果与预期结果相符。接下来，将继续在CHDPAH动物模型中验证上述lncRNA高表达与肺动脉高压发生的关系及涉及的相关信号通路，为临床先心病合并肺动脉高压的震诊断和治疗靶点提供依据。