线粒体自噬新的调控分子：lncRNAs及其生物网络构建

Mitophagy plays important roles in diverse cardiovascular diseases. However, the upstream molecular mechanisms of mitophagy is still unclear. Long non-coding RNAs (lncRNAs) contributes to the process of cardiovascular diseases, but the role and mechanisms of lncRNAs on mitophagy involved in cardiovascular diseases have not been explicitly delineated. In the previous study, we found that lncRNA AK007586, designated as myocardial infarction-related factor (MIRF), was up-regulated in the heart of mice after myocardial infarction (MI). Forced expression of MIRF can cause cardiac injury, and MIRF has the potential binding site for miR-26a and miR-140-3p, which have the predicted targets involved in mitophagy. Thus, we assume that MIRF regulates mitophagy by targeting miR-26a and miR-140-3p, and then contributes to MI. To address this hypothesis, we will perform the following experiments: 1) to reveal the role of MIRF on mitophagy during MI; 2) to examine the effect and mechanism of MIRF on miR-26a/140-3p; 3) to elucidate the underlying mechanism of miR-26a and miR-140-3p involved in the process of mitophagy; 4) to investigate the potential therapeutic role of targeting MIRF in MI; 5) to construct the lncRNAs regulatory network during MI by systematically excavating mitophagy-related lncRNAs. This project can not only expand the understanding of the mechanism and therapeutic strategy of myocardial infarction, but also provide a theoretical basis for the research and development of new drug for ischemic heart disease.

线粒体自噬在心血管疾病中发挥关键作用，但其上游机制仍不清楚。长链非编码RNA (lncRNA)参与心血管疾病的发生，但其对线粒体自噬的调控作用尚有待阐明。申请人前期发现lncRNA AK007586 (MIRF)在心梗小鼠心肌组织中表达升高且其过表达诱导心肌损伤，初步生物信息学预测发现MIRF具有miR-26a/140-3p的结合位点并预测其下游具有自噬相关靶点。我们假设MIRF通过miR-26a及miR-140-3p调控线粒体自噬，参与心肌梗死。本项目拟研究：1）MIRF对线粒体自噬的调控作用；2）MIRF对miR-26a/140-3p的调节作用；3）miR-26a/140-3p参与线粒体自噬的分子机制；4）靶向MIRF对心梗的治疗作用；5）系统挖掘线粒体自噬相关lncRNAs，构建lncRNAs调控网络。本项目将完善并拓展我们对心肌梗死发病机制的认识，为缺血性心脏病的防治提供理论依据。

为明确急性心肌梗死时非编码RNA的表达变化，利用GEO芯片数据及线粒体自噬数据库筛选调控线粒体自噬的lncRNAs，明确参与心肌自噬的lncRNAs差异调控网络及其作用机制，本项目采用在体动物疾病模型、转基因动物模型、离体细胞组织器官水平的实验研究， 揭示了lncRNA MIRF对线粒体自噬的调控作用及其分子机制：MIRF通过调控miR-26a，抑制线粒体自噬，促进心肌细胞凋亡，最终诱发心肌损伤。并阐明了miR-26a调控线粒体自噬的分子机制，即靶向线粒体自噬抑制基因Usp15。探索了靶向lncRNA MIRF对心肌梗死的保护作用，为临床心肌梗死的治疗及药物研发提供新靶点。此外，研究发现一系列长链非编码RNA，参与调控心血管系统疾病的病理生理过程，阐明了作用机制，并采用一定的干预手段，在实验动物水平验证了非编码的治疗作用。本项目共发表研究SCI论文19篇，培养青年科研工作者4人，博士研究生7人。项目负责人受邀参加国内外学术会议并做主旨报告5次，并获得龙江学者特聘教授，享受国务院政府特殊津贴。