Development of strategies for handling heart failure based on the molecular pathogenesis of cardiomyopathy

对心肌病新的致病基因进行了鉴定，并对各种心肌病相关突变进行了功能分析。我们发现了与心肌病相关的新的致病基因，如肥厚型心肌病中的Carp突变，扩张型心肌病中的星云突变和BAG3，以及肥厚型心肌病、扩张型心肌病和限制性心肌病中的myopalladin突变。对心肌病相关突变的功能研究表明，CARP突变增加了与肌动蛋白的结合，并增强了核转位。星云突变削弱了肌瘤的发生，而BAG3突变增加了对应激诱导的细胞凋亡的敏感性。Myopalladin突变损害了肌瘤的发生。此外，我们还揭示了心脏特异性肌球蛋白磷酸酶小亚基M21对心肌收缩的钙敏感性的分子机制。此外，我们还证明了化学增强的肌肉收缩钙敏感性SCH00013可以延长lama/C突变敲入小鼠扩张型心肌病的生存预后，提示调节钙敏感性是治疗/预防与心肌病相关的心力衰竭的新策略。

Identification of novel disease genes for cardiomyopathy and functional analyses of various cardiomyopathy-associated mutations were performed. We identified novel disease genes for cardiomyopathy, such that CARP mutations in hypertrophic cardiomyopathy, nebulette mutations and BAG3 in dilated cardiomyopathy,and myopalladin mutations in hypertrophic cardiomyopathy, dilated cardiomyopathy and restrictive cardiomyopathy. Functional studies of the cardiomyopathy-associated mutations revealed that CARP mutations increased binding to titin and enhance the nuclear translocation. Nebulette mutations impaired sarcomerogenesis and BAG3 mutations increased susceptibility to stress-induced apoptosis. Myopalladin mutations impaired sarcomerogenesis. In addition, we revealed a molecular mechanism for calcium sensitivity of cardiac contraction by heart-specific small subunit of myosin phosphatase, M21.Moreover, it was demonstrated that a chemical enhancing calcium sensitivity of muscle contraction, SCH00013, could prolong the survival prognosis of dilated cardiomyopathy in lamina/C mutation knock-in mice, suggesting that the regulation of calcium sensitivity is a novel therapeutic/preventive strategy for heart failure associated with cardiomyopathy