Syntaxin 12/13 敲除小鼠心衰机制及干预研究

我国约有一千两百多万心衰患者，心衰患者5年生存率仅为50%，尽管心衰的发病机制复杂，心肌代谢异常和能量稳态紊乱是不同原发性心衰的共同作用途径。因此，利用心衰相关的能量代谢紊乱动物模型，研究相关机制及其干预策略，有着极大的基础研究和临床应用价值。前期工作中，我们利用Syntaxin 12/13敲除小鼠和斑马鱼敲减模型，发现基因缺失导致心衰，通过细胞水平的机制探讨发现，Syntaxin 12/13敲除影响线粒体形态和功能，表现出心肌动作电位频率变慢的心衰表型；此外，体外利用心肌细胞原代培养模型，发现特异抑制线粒体功能，可以重复Syntaxin 12/13敲除的心肌细胞的电生理表型，提示Syntaxin 12/13基因心脏特异性敲除小鼠是一个心衰能量代谢紊乱的动物模型。基于前期的研究基础，项目将深入探讨Syntaxin 12/13心衰模型的机制及干预策略，为干预心衰能量代谢紊乱提供临床参考意见。

There are more than 12 million heart failure patients in China, and the 5-year survival rate of heart failure patients is about 50%. Although the pathogenesis of heart failure is complex, the abnormal homeostasis of myocardial energy metabolism is the common pathway of various primary heart failure. Therefore, animal models with energy metabolic disorder are of great value to study the related mechanisms and intervention strategies. Based on our pilot studies, the knockout mice and knockdown zebrafish models of Syntaxin 12/13 showed heart failure. At the cellular level, we found that Syntaxin 12/13 deficiency affected mitochondrial morphology and function, and caused a heart failure phenotype with a slower frequency of myocardial action potential. Moreover, using the primary culture model of myocardial cell in vitro, we found that the inhibition of mitochondrial function could mimic the electrophysiological phenotype of Syntaxin 12/13-knockout myocardial cell. Thus, Syntaxin 12/13-knockout mice was demonstrated as a good animal model of heart failure with energy metabolic disorder. This project will further explore its mechanism of heart failure and intervention strategies for clinical intervention.