Molecular Mechanisms of Dystrophic Cardiomyopathy

营养不良性心肌病的分子机制 摘要 心血管疾病仍然是美国死亡和残疾的主要原因。杜氏肌 肌营养不良症（DMD）是由肌营养不良蛋白基因突变引起的遗传性疾病，其影响肌营养不良蛋白基因的结构和功能。 心脏和骨骼肌的功能。心力衰竭已成为DMD死亡的主要原因 患者我们的目标是了解营养不良性心肌病的分子机制， 开发新的治疗策略来治疗这种疾病。 我们首次发现CIP是一种新的心肌细胞富集蛋白， 调节肥大和扩张的心脏。CIP与抗肌萎缩蛋白发生物理相互作用，其突变导致 DMD重要的是，我们观察到CIP过表达保护DMD小鼠（Mdx）免受心肌病。这些 令人兴奋的发现已经将CIP鉴定为营养不良性心肌病途径的新组分。在这 在这项研究中，我们将定义CIP作用的分子本质，并测试这种蛋白质在治疗中的潜力。 保护心脏免于发展为营养不良性心肌病。具体而言，我们将： 1)明确CIP在营养不良性心肌病和心力衰竭中的作用机制; 2)测试CIP在营养不良性心肌病中的治疗潜力; 3)检验CIP介导营养不良性心肌病中氧化应激信号通路的假设。 本申请中提出的研究将对DMD心肌病的发病机制产生新的见解。 此外，我们将证明，治疗是一个可行的战略，以治疗营养不良性心肌病，在这两个 鼠和人疾病模型。

MOLECULAR MECHANISMS OF DYSTROPHIC CARDIOMYOPATHY Abstract Cardiovascular diseases continue to be a leading cause of death and disability in USA. Duchenne Muscular Dystrophy (DMD) is a genetic disorder caused by mutations in the dystrophin gene that affects the structure and function of both cardiac and skeletal muscles. Heart failure has become a leading cause of fatalities in DMD patients. Our goal is to understand the molecular mechanisms underlying dystrophic cardiomyopathy, and to develop novel therapeutic strategies to treat this disease. We have first discovered CIP as a novel cardiomyocyte-enriched protein and we showed CIP is dynamically regulated in hypertrophic and dilated hearts. CIP physically interacts with dystrophin, mutation of which causes DMD. Importantly, we observed that CIP overexpression protects DMD mice (Mdx) from cardiomyopathy. These exciting findings have identified CIP as a novel component of the dystrophic cardiomyopathy pathway. In this study, we will define the molecular nature of CIP action and test the therapeutic potential of this protein in protecting the heart from developing dystrophic cardiomyopathy. More specifically, we will: 1) define the functional mechanism of CIP in dystrophic cardiomyopathy and heart failure; 2) test the therapeutic potential of CIP in dystrophic cardiomyopathy; 3) test the hypothesis that CIP mediates the oxidative stress signaling pathway in dystrophic cardiomyopathy. Studies proposed in this application will yield new insights into the pathogenesis of cardiomyopathy in DMD. Furthermore, we will demonstrate that therapy is a viable strategy to treat dystrophic cardiomyopathy in both murine and human disease models.