HIPK1下调介导运动诱导的生理性心肌肥厚及其机制研究

心力衰竭是多种心脏疾病的终末阶段，目前缺乏治愈的方法。运动诱导的生理性心肌肥厚对于心力衰竭具有保护效应。但是，生理性心肌肥厚的发生机制尚未清楚。我们在前期工作中发现，HIPK1在运动诱导的生理性心肌肥厚中表达下调；HIPK1敲低促进心肌细胞增殖。本项目将结合慢病毒过表达和干扰载体以及心肌特异性敲除和过表达小鼠，在细胞水平和动物水平实施功能实验，明确HIPK1与运动诱导生理性心肌肥厚的关系。在分子机制上，鉴于已知MicroRNA-222对HIPK1的调节以及初步数据表明C/EBPβ可能是HIPK1的下游分子，我们将明确HIPK1是否介导了MicroRNA-222的功能；明确HIPK1下游调控机制；阐释HIPK1如何调控C/EBPβ；明确HIPK1是否能够防治心力衰竭。本项目将阐明HIPK1在运动诱导的生理性心肌肥厚中的作用及分子机制，为防治心力衰竭提供新靶点。

Heart failure (HF) is the end stage of cardiovascular disease and the main cause for HF patients’ death. It still lacks therapy for HF. Exercise could promote cardiomyocyte growth and play protective roles for HF. But the mechanism for exercise induced physiological cardiac hypertrophy is unknown. In our previous research, we found that homeodomain-interacting protein kinase 1( HIPK1 ) was down-regulated in exercised hearts. Furthermore, the knockdown of HIPK1 increased cardiomyocytes proliferation. These data indicate that HIPK1 might be a potential regulator for exercise induced physiological cardiac hypertrophy. In the present project, we will identify the role of HIPK1 in exercise induced physiological cardiac hypertrophy through both in vivo and in vitro loss-of-function and gain-of-function experiments. Swimming induced cardiac hypertrophy model will be used in vivo with transgenic mice and AAV9 virus injection. Primary cardiomyocyte proliferation and hypertrophy model will be used in vitro with HIPK1 overexpressing lentivirus and HIPK1 interference lentivirus infection. Mechanistically, based on microRNA-222 and HIPK1 double knockout mice, we will elucidate the regulation of microRNA-222 to HIPK1 in exercise induced cardiac physiological hypertrophy. Secondly, based on previous study, we propose that C/EBPβ might be the downstream gene of HIPK1 in cardiomyocyte. Next, we will perform rescue experiments in vitro and in vivo to identify the regulation of HIPK1 to C/EBPβ in exercise induced physiological cardiac hypertrophy. Overall, our project will prove that the down-regulation of HIPK1 contributes to exercise induced physiological cardiac hypertrophy and provide novel therapeutic targets for HF therapy.