组蛋白赖氨酸特异性去甲基化酶1（LSD1）对压力负荷所致心肌重构和纤维化的调控作用及其机制研究

心肌肥厚和间质纤维化相互作用调控压力负荷所致心功能损伤并最终导致心衰，本实验室前期研究发现：组蛋白赖氨酸特异性去甲基化酶1(LSD1)调控上皮间质转换，但尚不清楚LSD1是否通过TGF-β1在压力负荷所致的心衰进程中发挥作用，因此本项目探讨：1）腺病毒中介的LSD1上调和下调是否通过TGF-β1通路调控离体乳鼠心肌细胞肥大和心肌成纤维细胞活化；2）心肌细胞特异性LSD1条件性基因敲除对压力负荷所致心肌肥厚和纤维化进程的影响；3）含Postn-CreER和Rosa-tdTomato的心肌活化的肌成纤维细胞特异性LSD1条件性基因敲除对压力负荷所致心肌肥厚和纤维化的调控作用；4）RNA-seq和蛋白质组学分析确定上述基因敲除小鼠压力负荷致心衰进程的确切调控因子；通过此实验设计确定：LSD1通过TGF-β1信号通路调控心肌肥厚和纤维化以致心衰的机制和新的作用靶点，为临床相关疾病治疗提供新思路。

The interaction between cardiac pressure-overload-related hypertrophy and interstitial fibrosis plays a key role in mediating cardiac pump dysfunction and heart failure. Our previous studies have shown that the histone lysine specific demethylase I(LSD1) may regulate the TGF-β1 related endothelial-mesenchymal transition(EMT) pathway in gastric cancer cells. However, it is not clear whether LSD1 may play a role in pressure overload induced cardiac dysfunction and fibrosis through TGF-β1 pathway. Therefore, in the current study, we will try to determine that： 1) the role of adenovirus-induced LSD1 overexpression and downregulation in Ang II, PE or ET-1-triggered neonatal cardiomyocyte hypertrophy or myofibroblast transition; 2) generation of cardiac specific LSD1 Cre-LoxP conditional knockout mice and characterization of the role of this mouse model in TAC-induced cardiac hypertrophy and fibrosis; 3) generation of Postn-CreER and Rosa-tdTomato-mediated myofibroblast-specific LSD1 knockout mice and characterization of the role of this mouse model in TAC-induced cardiac hypertrophy and fibrosis. 4) further characterization of both LSD1 KO mouse models using RNA-Seq and proteomics methods after TAC to search for more new targets. Through the study design, we will evaluate whether the role of LSD1 in pressure overload-induced cardiac hypertrophy, fibrosis and heart failure is through TGF-β1 pathway and would like to find some new therapeutic targets for this cardiac disease.