circRNA调控心肌梗死后心肌细胞焦亡的分子网络及干预研究

Pyroptosis is a new type of programmed cell death caused by inflammation. Recent studies uncovered that the inflammation in myocardial infarction may lead a large number of myocardial cell to pyroptosis, and thus inhibiting pyroptosis is expected as the new direction of the treatment of myocardial infarction. But the molecular mechanism of cardiomyocyte pyroptosis is still not clear. CircRNAs is one kind of non-coding RNA with cyclic structure, which has been proved to be closely related to many diseases. In the preliminary study, we found that circRNA-30287 was significantly upregulated in infarcted tissues by microarray screening, and its expression was positively correlated to focal pyroptosis factors caspase-1 and GSDMD expression, suggesting that circRNA-30287 as an important factor for myocardial pyroptosis. This project will employ molecular cloning, luciferase and other methods to verify: (1) whether circRNA-30287 is involved in the regulation of cardiomyocyte pyroptosis in myocardial infarction; (2) revealed that circRNA-30287-miRNAs-CASP1/GSDMD signal pathway mediates cardiomyocyte pyroptosis; (3) whether circRNA-30287 will become a new target for myocardial protection. In this study, we will find a new target to inhibit the pyroptosis of myocardial cells, so as to reduce the occurrence of serious complications such as heart failure after myocardial infarction.

细胞焦亡是一种由炎症反应引起的细胞程序性死亡。新近研究发现心肌梗死时局部炎症可导致心肌细胞的焦亡，因此抑制焦亡有望成为心肌梗死治疗的新方向，但心肌细胞焦亡的分子机制仍不清楚。CircRNAs是一类环状结构的非编码RNA，已证实与多种疾病发生密切相关。在前期研究中我们通过芯片筛选发现circRNA-30287在心肌梗死边缘区组织中显著上调，且其表达水平与caspase-1和GSDMD表达呈正相关，提示其是心肌细胞焦亡的重要调控因子。本课题拟运用分子克隆、Luciferase等技术验证（1）circRNA-30287是否调控心肌梗死时心肌细胞焦亡的发生；（2）揭示circRNA-30287通过靶向调控miRNAs-CASP1/GSDMD分子网络诱导心肌细胞焦亡；（3）circRNA-30287是否可以成为心肌保护的新靶点。本研究将发现抑制心肌细胞焦亡的新靶点，将为临床心肌梗死的防治提供新思路。

本项目严格按项目计划书执行，已完成项目预期研究目标和考核指标，并取得了预期的研究成果。完成项目计划研究内容，阐明了临床心肌梗死疾病中心脏功能损伤的重要机制。发现CircHelz通过miR-133-3p/NLRP3通路介导心肌梗死小鼠心肌细胞的细胞焦亡病理生理过程，是心脏发生缺血性损伤的重要机制之一。揭示了心肌梗死过程中缺血性心律失常和心脏炎性反应及纤维化损伤的分子调控机制。阐明FGF21通过调控转录因子EGR1，一方面调控心肌细胞离子通道（NaV1.5和Kir2.1）的表达和功能，抑制缺血性心律失常的发生；另一方面调控心肌细胞中炎症因子及纤维化相关因子的表达，从而抑制心肌细胞炎症反应及纤维化损伤，阐明FGF21对心肌梗死小鼠心脏的保护作用及分子机制。完成科研成果目标，共发表SCI收录文章7篇（J Mol Cell Cardiol. 2021；Journal of Advanced Research. 2021；Basic Research in Cardiology.2020；Front Pharmacol. 2021；Eur J Pharmacol. 2021；Acta Pharmacol Sin. 2019；Acta Pharmacol Sin. 2020），其中JCR分区Q1区3篇，Q2区4篇；影响因子>10以上科研文章2篇，最高影响因子17.165。完成研究生毕业论文7篇（博士毕业论文1篇，硕士毕业论文6篇）。发表国际会议摘要3篇。完成人才培养目标，共培养博士研究生6名（毕业1名，招收5名），硕士研究生18名（毕业6名；硕博连读2名；招收10名）。课题组骨干成员和博士研究生参加国际学术交流会议，获得优秀论文二等奖2项。完成学术成果会议交流，参加国际会议1次，会议摘要被接收做会议海报展示。参加国内学术会议3次，分别担任青年优秀论文评选评委、大会主持，并做大会报告。