分泌性蛋白Zinc-a2-glycoprotein在遗传性扩张型心肌病发生发展中的作用与机制研究

家族遗传性扩张型心肌病是遗传性心肌病中较多见的一种。除了心脏移植外，目前并无有效治疗手段，急需研发新的治疗方法。目前已知很多基因的点突变都可导致扩张型心肌病，但具体的疾病分子机制并不清晰。申请人前期研究建立了TNNT2基因突变导致的遗传性扩张型心肌病-人类多能干细胞-心肌细胞疾病模型及同一突变的小鼠扩张型心肌病模型，并发现Zinc-a2-glycoprotein（ZAG）表达在疾病早期就显著下调。申请人进一步建立了ZAG心肌组织特异性敲除小鼠，发现ZAG缺失可以导致心脏扩张表型。因此我们推测ZAG与遗传性扩张型心肌病的发病机制密切相关，可能成为干预疾病的新靶点。本课题拟全面阐明ZAG与心肌细胞能量代谢及扩张型心肌病的关系及其分子机制，并在不同扩张型心肌病小鼠模型上验证回补ZAG治疗遗传性扩张型心肌病的价值。本项目有助于深入理解家族遗传性扩张型心肌病的发病机制，并为其治疗提供新的思路与方法。

Dilated cardiomyopathy (DCM) is a common form of familial inherited cardiomyopathy. New therapeutic methods are required since there are currently no effective treatments except for heart transplantation. Although many mutations in various genes are known to cause familial DCM, the detailed molecular mechanism of the disease is not clear. We established both human pluripotent stem cell (hPSC) and mouse model of the TNNT2 mutation induced familial DCM in our previous study. We found that Zinc-a2-glycoprotein (ZAG) was significantly down-regulated in both hPSC and mouse TNNT2 mutation induced DCM models in an early stage. We further established cardiac tissue-specific ZAG knockout mouse and found that ZAG deficiency directly led to DCM after week 12. Based on these data, we hypothesize that ZAG is closely acoosciated with the development of DCM and could be a new therapeutic taget gene for the disease. This study would be helpful for us to better understand the disease mechanism as well as provide new methods for the treatment of of inherited DCM.