Hippo信号转导通路在肥厚性心肌病中的作用和分子机制研究

Hypertrophic cardiomyopathy is one of hereditary cardiac diseases and the inappropriate ventricular hypertrophy is the overt pathological manification, which leads to cardiac dysfunction and heart failure. Cardiac hypertrophy is mostly caused by genetic mutations. Hippo/MST-Yorkie(YAP2) signaling pathway, an conserved pathway from Drosophila to mammals, plays an important role in the regulation of cell growth and organ size. As the core effector of this pathway, YAP2 was found to be activated in the samples of hypertrophic cardiomyopathy in our previous work. Cardiac specific YAP2 transgenic mice developed myocardial hypertrophy.We also observed that overexpression of YAP2 increased the cell size in the primary cultured cardiomyocytes. Moreover, we also found that YAP2 activates PI3K/Akt pathway. Base on these observations, we aim to further explore the function of YAP2 in the development of cardiac hypertrophy by using YAP2 cardiac-specific transgenic and conditional knock out mice, and to elucidate the underlying molecular mechanism of hypertrophic cardiomyopathy, with the implication of the novel therapeutic avenue for the hypertrophic cardiomyopathy.

肥厚性心肌病是一种遗传相关性心血管疾病，常表现为不适当的心室肥厚，单基因突变即可致病，可导致心功能不全或心血管死亡,其机制尚不清楚。阐明心肌肥厚发生的机制有利于该病的预防及治疗。Hippo(MST)-Yorkie(YAP)信号转导通路，在果蝇到哺乳动物中保守存在，该通路对于细胞生长和器官大小调控发挥重要作用，既往报道提示YAP2可以引起心肌肥厚。我们在前期实验中发现在肥厚性心肌病临床标本中YAP2活性升高；在心脏特异性YAP2转基因小鼠中出现增生性心肌肥厚；在原代心肌细胞中YAP2可以促进细胞增生；并且在分子水平上发现YAP2激活了PI3K/AKT这一促生长信号通路。在此基础上，我们拟在YAP2转基因和基因敲除小鼠上制备肥厚性心肌病模型并结合临床标本，深入地研究YAP2在心肌肥厚过程中起到的作用及其分子机制，阐明肥厚性心肌病发病的分子机理，为临床肥厚性心肌病的诊治提供理论基础和可能的治疗。

肥厚性心肌病是一种遗传相关性心血管疾病，常表现为不适当的心室肥厚，可导致心功能不全或心血管死亡，其机制尚不清楚。Hippo(MST)-Yorkie(YAP)信号转导通路，该通路对于细胞生长和器官大小调控发挥重要作用。在心脏特异性YAP2转基因小鼠、基因敲出小鼠与原代心肌细胞实验中证实 YAP2 激活了 PI3K/AKT 这一促生长信号通路促进心肌肥厚。通过研究肥厚性心肌病的发病机理，有助于提高该病的诊疗水平，对稳定患者病情、决定医疗干预的时机、降低病死病残率十分有益，社会价值和经济价值明显。