靶向Atgs的microRNA通过抑制心肌细胞自噬促进心肌肥大的作用与机制研究

自噬作为胞内物质降解途径对维持心肌细胞稳态具有重要作用。我们的前期研究和近年来文献报道表明，自噬功能受损是导致心肌肥大的关键因素，然而调控心肌自噬的相关机制尚不明确。microRNA作为一类重要的非编码RNA，可在转录后水平广泛影响细胞功能。最近我们利用高通量测序筛查到miR-34c等多个在心肌肥大中异常表达的microRNA，并初步证实其通过靶向调控自噬相关基因Atgs抑制细胞自噬。据此我们提出假设：microRNA表达异常可引起自噬水平降低从而介导心肌肥大，通过调控microRNA可增强自噬并发挥对心肌肥大的保护作用。本项目拟进一步在体内外干预miR-34c等靶向Atgs的候选microRNA，重点围绕对心肌细胞自噬的影响，阐明其与心肌肥大的关系和具体分子机制，探讨调控microRNA激活自噬进而防治心肌肥大的新策略，为以microRNA为靶标的心血管疾病药物研发提供更充分的科学依据。

Autophagy, a lysosome-dependent pathway for the degradation of cellular components, plays essential roles in maintaining the homeostasis of cardiomyocytes. Our previous studies and recent literatures have revealed that impaired autophagy contributes to the development of cardiac hypertrophy. However, the mechanisms controlling cardiac autophagy remain to be elucidated. As an important group of non-coding RNAs, microRNAs have been proved to regulate a diversity of cellular functions at post-transcriptional level. Lately, we searched the differential expressed non-coding RNAs in cardiac hypertrophy by using the high-throughput sequencing technology, and observed that the levels of several microRNA species including miR-34c, were significantly increased. Moreover, our preliminary investigations indicated that these microRNAs could target various autophagy-related genes thereby repressing autophagy. Based on these findings, a hypothesis is proposed: the abnormal expression of microRNAs leads to decreased autophagy and subsequently provokes cardiac hypertrophy, while interfering microRNAs can protect against cardiac hypertrophy by enhancing autophagy. In the present study, we will further modulate miR-34c and other Atgs-targeted microRNAs both in vitro and in vivo, to investigate the potential influences on cardiac hypertrophy with a focus on their roles in regulating autophagy and clarify the underlying mechanisms. Our research will help to validate the new therapeutic strategy against cardiac hypertrophy via promoting microRNA-mediated autophagy, and facilitate the development of novel agents for cardiovascular diseases by targeting microRNAs.