mTOR-自噬参与特定miRNA介导的硫化氢心肌保护作用的研究

项目名称： mTOR-自噬参与特定miRNA介导的硫化氢心肌保护作用的研究

项目编号： No.81200181

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 肖健

作者单位： 中国人民解放军第二军医大学

项目金额： 23万元

中文摘要： 心肌细胞自噬在心肌缺血再灌注（IR）损伤中扮演重要角色。在自噬的调控机制中，雷帕霉素靶蛋白（mTOR）可能起关键作用。我们前期研究发现硫化氢可下调IR心肌细胞自噬相关基因（Atg）的表达，并上调p-mTOR蛋白。此外应用miRNA芯片在IR和对照组之间筛选出差异显著且心肌特异表达的miRNA（miR-199a、miR-204和miR-30）。生物信息学显示上述miRNA的靶基因包括多种Atg及mTOR亚单位。初步研究表明部分miRNA可被硫化氢调控，提示硫化氢可能通过miRNA，调控mTOR-自噬通路。本项目将以mTOR-自噬为切入点，通过上调/下调上述miRNA，观察其对自噬相关靶基因的调控，明确硫化氢如何通过调控miRNA干预mTOR-自噬通路，减少心肌细胞自噬发生。本研究有助阐明硫化氢调控mTOR-Atg表达、抑制心肌细胞自噬的可能机制，为硫化氢相关药物研发及临床心肌保护提供新思路。

中文关键词： 自噬；miRNA；mTOR；心肌细胞；缺血再灌注

英文摘要： Many studies has revealed that autophagy plays a key role in myocardial IR injury and can be regulated by mammalian target of rapamycin (mTOR), which is crucial in atuophagy regualtion. Our preliminary data demonstrated that hydrogen sulfide (H2S) down-regulated the expression of autophagy-related gene (Atg) and up-regulated the level of p-mTOR protein. Moreover, by using miRNA chip, it has been provided evidence that miRNA (miR-199a, miR-204 and miR-30) played important roles in myocardial IR injury and these miRNA could be regulated by H2S. According to bioinformation, the target genes of these miRNA included multiple Atgs and mTOR subunit. We hypothesised that H2S could inhibit autophage by modulating the specific miRNA through regulating mTOR-autophagy pathway. This study is designed to investigate whether specific miRNA could regulate mTOR-autophagy associated targert genes and how H2S could inhibit autophagy through miRNA pathway by modulating the specific miRNA.The proposed study will significantly advance our current understanding of the mechanisms of H2S regulating mTOR-Atg signaling and inhibiting myocardial autophagy. Results gained from this study will provide new vision and help with the development of novel therapies for clinical cardioprotection. Thus, this proposed study has theoretically signifi

英文关键词： autophagy；miRNA；mTOR；myocardiocyte；ischemia reperfusion