心肌梗死中差异表达lncRNAs的筛选及其功能研究

Long non-coding RNAs (lncRNAs) are defiend as non protein-coding transcripts lager than 200 nucleotides. Recent studies indicate that lncRNAs play important roles on cardiovascular diseases. Our previous study has shown that 958 lncRNAs are differentially expressed in myocardium of myocardial infarction. The expression of lncRNA-Meg3 is increased significantly in myocardial tissue of myocardial ischemia. Preliminary studies have indicated that silencing Meg3 could inhibit myocardial apoptosis and induce angiogenesis. One of the potential targets is p53. Our preliminary data have clearly demonstrated that lncRNA-Meg3 could regulate myocardial infarction. In this project, through different research levels including molecular, cellular, animal model and cardiac patient, we will (1) screen the differentially expressed lncRNAs in myocardial infarction; (2) uncover the lncRNA-Meg3 function on apoptosis, angiogenesis, calcium maintenance, cardiac electrophysiology, and the target’s regulation network; (3) illustrate the therapeutic efficacy with non-viral mincircle silencing Meg3 on myocardial infarction; (4) detect the expression pattern of Meg3 in patients’ blood samples and discuss the potential of Meg3 as a novel biomarker of myocardial infarction.

长链非编码RNAs（lncRNAs）是一类大于200bp、不编码蛋白质的转录RNAs，最近的研究表明lncRNAs在心血管疾病中发挥重要作用。本项目初步研究结果表明，在心肌梗死的心肌组织中958个lncRNAs呈现差异表达。其中，lncRNA-Meg3在心肌梗死的心肌组织中高水平表达。沉默Meg3能够抑制缺氧诱导的心肌细胞凋亡、促进血管生成因子表达，p53是其潜在的靶基因之一。因此，前期实验结果揭示Meg3是调节心肌梗死的重要lncRNAs之一。本项目从分子、细胞、动物模型和疾病患者等多水平研究，将（1）筛选心肌梗死差异表达的lncRNAs；（2）详细阐述Meg3在凋亡、血管发生、钙维持和电生理方面调控心肌梗死的机制，明确靶基因的调控网络；（3）探讨利用非病毒基因治疗载体沉默Meg3治疗心肌梗死的潜能；（4）检测外周血Meg3的表达规律，确定其做为心肌梗死标志分子的可能性。

心肌梗死已经成为一个十分突出的公共卫生问题和社会问题，基因治疗为心肌梗死的防治带来了新的希望。长链非编码RNA（long noncoding RNA, lncRNA）在心血管系统中发挥关键的功能作用，并可能有潜力作为心脏疾病的治疗靶标。本研究通过构建小鼠心肌梗死模型，采用高通量转录分析策略筛选在心肌梗死组织与正常心肌组织中差异表达的lncRNA，并进一步研究功能性lncRNA与心肌梗死发生发展的关系，以期确定新的可能作为心肌梗死治疗靶点的lncRNA。研究心梗后表达显著上调的lncRNA-Meg3，发现lncRNA-Meg3可以与RNA结合蛋白FUS形成复合体促进心肌细胞凋亡；心肌内干涉lncRNA-Meg3可以改善心梗后的心脏功能；lncRNA-Meg3可作为心肌损伤标志分子，有望作为心肌梗死的基因治疗靶标。