GRIM-19协同STAT3在促进心肌细胞增殖保护梗死心肌中的作用及机制研究

增强心肌细胞增殖能力促进心肌细胞再生是恢复心肌梗死后心功能理想的治疗方法，是再生医学的研究热点。本项目组前期研究心脏线粒体复合体I一重要因子即细胞死亡调节因子GRIM-19 (gene associated with retinoid-interferon-induced mortality 19)时，发现适度下调GRIM-19可使心肌细胞重新进入细胞周期，并上调c-Myc和HIF1α的表达。由此推测适度下调GRIM-19可增强心肌细胞增殖修复梗死心肌。本项目拟利用条件性可诱导心肌特异性GRIM-19和STAT3敲除小鼠旨在阐明适度下调GRIM-19可以通过与STAT3协同调控c-Myc转录活性促进心肌细胞增殖和抗凋亡能力达到心肌梗死后修复心肌的作用及HIF1α作为STAT3的协同因子在其中的作用模式。本项目的实施可望揭示心肌梗死后心肌再生一新调控机制，为临床应用提供理论依据。

To enforce the re-entry into cell cycle of cardiomyocytes for myocardial regeneration to compensate a significant loss of cardiomyocytes is an ideal method to repair cardiac injury after myocardial infarction (MI), which remains a hot topic for regeneration medicine. Our preliminary data suggest that GRIM-19 (gene associated with retinoid-interferon-induced mortality 19) is critical for cardiomyocyte proliferation which involves mediating HIF1α and c-Myc up-regulation. This set of data suggests GRIM-19 is an important regulator of self-renew for cardiomyocytes. Thus, in the present proposal, we will utilize newly generated tamoxifen inducible cardiac specific (under myh6-Cre) GRIM-19 and STAT3 (loxP) knock-out mice models and use a MI model to elucidate the following scientific questions: 1) moderate down-regulation of GRIM-19 can trigger cardiomyocyte proliferation and generate newer cardiomyocytes, which would significantly improve post-MI remodeling; 2) STAT3 is responsible for GRIM-19 induced cardiac regeneration process which involves increased c-Myc transcription activity; 3) HIF1α as a cofactor of STAT3 facilitates the effect of GRIM-19 on cardiac repair. Completion of this research project would not only further enhance our understand of cardiac regeneration and but also provide new therapeutic approach for treating patients with MI.