长非编码RNA-DQ402472调控心肌细胞凋亡影响高脂膳食诱导I/R心肌易损性及α-亚麻酸干预研究

High-fat diet (HFD) may aggravate the myocardial susceptibility to ischemia/reperfusion (I/R) injury, but the pathogenesis underlying is unknown. Long non-coding RNA (LncRNA) can regulate important signal transduction, and be involved in the pathogenesis of I/R injury. Our preliminary study based on RNA-seq has obtained a differential expressed LncRNA-DQ402472 related to HFD in rat I/R myocardial tissue, and the expression of DQ402472 was found to be ehanced in the I/R myocardial tissue of rats fed with high fat. Based on these preliminary results, we will use the technology of RNA interference to inhibit the expression of DQ402472 at both the integral and cellular levels, and explore the mechanism by which DQ402472 regulates myocardial cell apoptosis and influences HFD myocardial susceptibility to I/R injury. Moreover, we will apply the methods of RNA pull-down and RIP to find the target, which can directly interact with DQ402472. Also, we will adopt the technologies of gene transfection and RNA interference to intervene the expression of DQ402472 and its target, which can reproduce or block the biological function of DQ402472, observe the response of rats to I/R stimulus, and verify the effect of DQ402472 on myocardial susceptibility to I/R injury and its mediation by the target. Based on these, we will further study the effect of alpha-linolenic acid (ALA) intervention on HFD myocardial susceptibility to I/R injury and its relationship to the biological function mediated by DQ402472. These results will provide new targets for the prevention and treatment of HFD myocardial susceptibility to I/R injury and also give evidence for the control strategy of dietary ALA.

高脂膳食（HFD）致缺血再灌注（I/R）心肌易严重受损，其机制未明。长非编码RNA（LncRNA）可调控重要信号转导，参与I/R心肌损伤。前期RNA测序比对得到大鼠I/R心肌组织中与HFD相关差异表达的LncRNA-DQ402472，并发现其在HFDI/R心肌中表达升高，在此基础上，拟采用细胞和整体水平RNAi下调DQ402472表达，观察其对心肌细胞凋亡和HFDI/R心肌易损性的影响；通过RNA pull-down和RIP等方法寻找与其直接作用的靶标；应用基因转染和RNAi干预DQ402472和靶标以实现DQ402472功能的再现或阻断，观察大鼠对I/R的反应性，对其调控I/R心肌易损性及靶标的真正介导作用再验证；并借此研究α-亚麻酸(ALA)干预对HFDI/R心肌易损性的影响及其与DQ402472介导的生物学功能间的关系。为HFDI/R心肌易损防治新靶点及膳食ALA的防治策略提供依据。

高脂膳食（HFD）致缺血再灌注（I/R）心肌易严重受损，其机制未明。长非编码RNA（Lnc RNA）可调控重要信号转导，参与I/R心肌损伤。前期RNA测序比对得到大鼠I/R心肌组织中与HFD相关差异表达的LncRNA-DQ402472，并发现其在HFDI/R心肌中表达升高，干扰DQ402472表达可抑制心肌细胞凋亡，改善HFDI/R心肌易损性；进一步研究发现DQ402472 shRNA抑制长期高脂膳食引起的I/R心肌GSK-3β磷酸化水平的下降和细胞凋亡，从而对高脂膳食IRI心肌易损起保护作用。α-亚麻酸(ALA)干预可改善I/R心肌易损性，与其对P2X7R / NF-κB信号通路抑制，改善I/R心肌炎症相关。为HFDI/R心肌易损防治新靶点及膳食ALA的防治策略提供依据。课题完成时发表标注论文21篇，其中SCI论文20篇，中文核心论文1篇。专利5项，获国家级奖项3项，培养研究生3名。在本项目实施的基础上，入选江西省百千万人才工程人选和江西省杰出青年（井冈学者）。