病理性心肌肥厚严重损害心脏结构和功能，其防治策略是当今研究热点。申请者发现脂肪因子CTRP3能够显著改善压力负荷型心肌肥厚，但下游调控通路尚不明确。预实验结果显示：心肌肥厚时，CTRP3过表达显著上调心肌PGC-1α及线粒体功能相关分子表达，抑制活性氧生成；且CTRP3敲除显著下调肥厚心肌线粒体未折叠蛋白反应（UPRmt）主要调控因子ATF5和多种效应因子的表达。激活UPRmt可以维持应激状态下线粒体内环境稳态，减轻压力负荷型心肌损伤，但机制研究十分匮乏。由此提出科学假说：CTRP3通过进一步激活UPRmt，改善心肌受损线粒体，减轻压力负荷型心肌肥厚。本项目拟采用基因敲除、病毒过表达、siRNA干扰等基因干预技术，通过离体心肌细胞与整体功能研究，验证CTRP3调控心肌细胞UPRmt的作用，阐明具体分子机制，为抑制肥厚心肌线粒体损伤提供新靶点，并促进CTRP3的心肌保护作用向临床应用发展。

Pathological cardiac hypertrophy causes severe damage to cardiac structure and function. The prevention or therapeutic strategy for it remains a research hotspot. The applicant’s prior research confirms that adipokine CTRP3 exerts a protective role against pressure overload induced cardiac hypertrophy, while the downstream signaling pathways are still unclear. Noteworthily, our preliminary experiment data showed that CTRP3 overexpression upregulated expression of PGC-1α and mitochondrial oxidative phosphorylation effectors and decreased production of reactive oxygen species in hypertrophic myocardium. Furthermore, the expression levels of ATF5—a key regulator of mitochondrial unfolded protein response(UPRmt) and several major effectors of UPRmt were downregulated in CTRP3-knockout mice hearts under pressure overload. Previous studies confirm that activation of UPRmt can maintain the cardiac mitochondrial homeostasis under stress, alleviating pressure overload induced cardiac injury. However, there is a lack of research on the mechanism of UPRmt. Based on these results, we hypothesize that adipokine CTRP3 further activates UPRmt to improve the damaged mitochondria in myocardium, thereby inhibiting pathological cardiac hypertrophy under pressure overload. This project is intended to construct in vivo pathological cardiac hypertrophy and in vitro cardiomyocyte hypertrophy models. We would use gene knockout, specific siRNA interference and gene overexpressing virus to intervene specific gene expression. Then the changes of relevant indicators would be observed and analyzed via basic experimental methods including localization, quantification, morphological analysis and so on to verify the regulation role of CTRP3 on UPRmt in cardiomyocytes, to clarify the underlining mechanisms. This study will provide new ideas for the inhibition of mitochondrial injury in hypertrophic myocardium and promote the transformation of CTRP3 into clinical application.