Molecular Mechanisms of Dystrophic Cardiomyopathy

营养不良性心肌病的分子机制 摘要 在美国，心血管疾病仍然是导致死亡和残疾的主要原因。杜兴肌肉 营养不良(DMD)是一种遗传性疾病，由dystrophin基因突变引起，影响结构和 心肌和骨骼肌的功能。心力衰竭已成为导致DMD死亡的主要原因 病人。我们的目标是了解营养不良性心肌病的分子机制，并 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丰富的蛋白质，我们证明了CIP是动态的 在肥大和扩张的心脏中受到调节。CIP与dystrophin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)免受心肌病的影响。这些 令人振奋的发现已经确定CIP是营养不良心肌病途径的一个新的组成部分。在这 在这项研究中，我们将确定CIP作用的分子性质，并测试该蛋白在 保护心脏免受营养不良性心肌病的侵袭。更具体而言，我们会： 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)检测CIP对营养不良性心肌病的治疗潜力； 3)验证CIP介导营养不良性心肌病氧化应激信号通路的假说。 这项申请中提出的研究将对DMD的心肌病的发病机制产生新的见解。 此外，我们将证明治疗是治疗营养不良性心肌病的一种可行策略。 小鼠和人类疾病模型。

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.