环状RNA（circ_0076631）靶向miR-214/133调控糖尿病心肌病的新机制

Diabetic cardiomyopathy (DCM) is one of diabetic complications, which is associated with myocardial injury and fibrosis, however, the exact pathogenesis is poorly understood. Recently, whether circRNA plays the critical role in DCM has been extensively discussed. Our preliminary results showed that cardiomyocytes treated with high glucose were accompanied with increased circ_0076631 level, decreased miR-214, increased caspase-1 and caspase-3, and aggravated apoptosis and pyroptosis; fibroblasts treated with high glucose were accompanied with increased circ_0076631 level, decreased miR-133, increased TGF-β1, and aggravated fibrosis. Therefore, we hypothesized that circ_0076631 regulated myocardial injury and fibrosis through targeting miR-214 and miR-133, respectively. In this project, we try to identify the role and molecular regulatory mechanism of circ_0076631 on DCM by biological information, transgenic technology and molecular biological technique both in vivo and in vitro.

糖尿病心肌病（DCM）是导致糖尿病患者死亡的重要并发症之一，其发生与心肌损伤和纤维化有关，但确切的发病机制尚未阐明。近来环状RNA在DCM中的重要调控作用已成为科学家关注的热点。我们前期研究发现：1）在高糖处理的心肌细胞中，circ_0076631表达增加，miR-214表达减少且其靶基因caspase-1和caspase-3表达增加，细胞焦亡、凋亡加重；2）在高糖处理的成纤维细胞中，circ_0076631表达也增加，miR-133表达减少且其靶基因TGF-β1水平增加，纤维化加重。因此我们假设：circ_0076631通过靶向miR-214和miR-133，从而分别调节心肌损伤与纤维化，进而影响DCM的发生发展。为验证这一假说，我们将联合运用生物信息、转基因和基因敲除、分子生物学等技术从离体和在体水平阐明circ_0076631在DCM中的作用与分子调控机制，并为其治疗提供新的靶点。

通过本项目研究揭示了环状RNA (circ_0076631，CACR) 对糖尿病心肌病的调控作用及其分子机制，为糖尿病心肌病治疗提供了新策略和新思路。我们证实了在高糖处理的心肌细胞中miR-214-3p可以与caspase-1靶向结合，CACR通过miR-214-3p/caspase-1调节AC16细胞焦亡。同时本项目还证实了长链非编码RNA Kcnq1ot1通过调控miR-214，进而调控其靶基因caspase-1，影响成纤维细胞焦亡和纤维化，最终影响糖尿病心肌病；并观察发现褪黑素通过抑制LncR-MALAT1，上调miR-141表达，抑制NLRP3 炎症小体和TGF-β1/Smad信号通路活化。此外，还发现miR-150能够通过调控TGF-β1/Smad信号通路，在糖尿病心肌病中发挥作用。本项目取得了预期的研究成果。已发表4篇SCI收录论文，影响因子均在5以上；本项目共培养了4名博士研究生，2名硕士研究生。