心肌细胞线粒体miRNA调控线粒体功能及线粒体自噬分子机制研究

MicroRNAs (miRNAs) are a class of small non-coding RNA and act as negative regulators of gene expression by inhibiting mRNA translation or promoting mRNA degradation. miRNAs can regulate cardiac function including the conductance of electrical signals, heart muscle contraction, heart growth and morphogenesis. In particular, miRNAs are involved in the pathogenesis of cardiac diseases, and manipulation of miRNAs can be developed to therapeutic targets Mitochondria provide the energy required for cardiomyocyte function and thus, the heart is enriched in mitochondria. Resent studies have suggested nuclear genome encoded miRNA be identified in mitochondrial, these miRNAa are termed 'mitomiRs'. The function of mitomiRs and the specific mechanism are still unclear. In our early studies, we have detected the miRNA profile from highly purified mitochondria from cardiomyocytes and revealed the role of miR-XX on mitochondrial function. This study will reveal mitomiRs profile in mitochondrial of cardimyocytes in physiological and pathological state. In addition, we also plan to investigate the molecular mechanism and signal pathway of miR-XX on mitochondrial gene expression, mitochondria function and mitophagy. At the same time, we will study the role of miR-XX in myocardial ischemic injury at animal level. Nowadays, cardiovascular diseases have become the key killer to people's health, so the research in this project is of great significance to further reveal the molecular mechanism involved in heart diseases and support theoretical evidence for their preventions and therapies.

miRNAs是一类非编码小RNA，近年来的研究显示miRNA在心脏中发挥重要作用，心脏中的miRNA异常表达与许多心脏疾病的发生相关。线粒体为心肌细胞提供其所需的能量，对于维持心脏的正常生理功能非常重要，最近有报道核基因编码的miRNA可以进入线粒体。但线粒体中的miRNA发挥什么功能、具体的作用机制尚没有系统研究。我们前期检测了心肌细胞线粒体中的miRNA，并初步揭示miRNA-XX具有调控线粒体功能的作用。本研究将揭示心肌细胞线粒体中miRNA在生理和病理状态下的表达情况；深入探讨miRNA-XX通过调控线粒体基因表达、线粒体功能、线粒体自噬，参与心肌细胞死亡的信号通路和分子机制。同时我们还将在整体动物水平研究miRNA-XX在心肌缺血损伤中的作用。通过以上研究将为阐明心肌细胞线粒体miRNA在心脏缺缺血性疾病中的作用及分子机理提供理论依据，为心脏疾病的预防、治疗提供新的靶点。

近年来的研究显示miRNA在心脏中发挥重要作用，心脏中的miRNA异常表达与许多心脏疾病的发生相关。线粒体为心肌细胞提供其所需的能量，对于维持心脏的正常生理功能非常重要，最近有报道核基因编码的miRNA可以进入线粒体。本项目通过基因芯片筛选获得心肌细胞线粒体中的miRNA表达谱，并对其中一个含量较为丰富的miRNA——miR-18a开展了深入研究。对其功能进行研究，发现miRNA-18a具有调控线粒体功能的作用。miR-18a在线粒体中可以通过结合线粒体基因组的D-loop区，抑制线粒体基因组复制，导致线粒体DNA含量降低及线粒体体氧化呼吸链蛋白含量减少，进而导致线粒体氧化呼吸链功能障碍。进一步揭示了miRNA-18a通过调控线粒体基因表达、线粒体功能参与调控线粒体自噬、心肌细胞死亡。我们还在整体动物水平研究发现miR-18a在心肌缺血损伤中发挥作用。缺血心肌组织中miR-18a表达上调，通过促进线粒体自噬及心肌细胞死亡，参与心肌缺血损伤。通过以上研究阐明了心肌细胞线粒体miRNA在心脏缺缺血性疾病中的作用及分子机理，为心脏疾病的预防、治疗提供新的靶点。