Cardiomyopathy in muscular dystrophies

描述(申请人提供)：这项工作的长期目标是了解基因定义的遗传性心肌病的机制，以便阐明人类心血管疾病的常见机制和设计治疗方法。这项建议集中在肌营养不良症中发生的心肌病，这些肌营养不良症与肌营养不良蛋白糖蛋白复合体(DGC)缺陷有关。心肌病在肌营养不良症患者中是一个越来越重要但尚未被研究的临床问题，通常会导致过早死亡。抗肌营养不良多糖是DGC中的中心跨膜蛋白，结合细胞内细胞骨架的抗肌营养不良蛋白和细胞外基质中的蛋白质。DGC在心肌细胞和血管平滑肌中都有表达，但每种组织在心肌病中的作用仍有很大争议。肌营养不良多糖的糖基化异常导致其作为细胞外基质受体的功能丧失，被认为是几种形式的人类肌营养不良症合并心肌病的原因。总的假说是，心肌细胞内通过肌营养不良蛋白聚糖从细胞骨架到细胞外基质的机械连接中断是直接导致糖基化缺陷性肌营养不良相关心肌病的主要机制。其具体目的是：1)研究肌营养不良的主要心脏功能障碍，以及骨骼肌和平滑肌功能障碍对心肌病严重程度和心脏机械功能的相对贡献。2)确定营养不良糖链破坏影响肌肉细胞结构/功能的细胞内在机制，以便确定治疗干预的靶点。糖基化缺陷和抗肌营养不良基因靶向的小鼠将被用来测试抗肌营养不良蛋白在与糖基化缺陷性肌营养不良相关的心肌病中的因果和组织特异性作用。在心肌细胞中的实验将确定心肌细胞功能障碍的细胞内在机制，这些机制是功能性肌营养不良蛋白聚糖缺乏导致心肌病的基础，并将为测试针对这些机制的治疗干预提供一个平台。由于DGC的改变也可以在其他几种形式的肌营养不良症和遗传性或获得性人类心肌病中看到，这项工作应该有助于我们对人类肌肉营养不良和心脏病的广泛理解。

DESCRIPTION (provided by applicant): The long term objective of this work is to understand the mechanisms of genetically defined inherited cardiomyopathies in order to shed light on common mechanisms and devise therapies for cardiovascular disease in humans. This proposal is focused on cardiomyopathies that occur in muscular dystrophies associated with defects in the dystrophin-glycoprotein complex (DGC). Cardiomyopathy is an increasingly significant, but understudied, clinical problem in muscular dystrophy patients, often resulting in premature death. Dystroglycan is the central transmembrane protein within the DGC, binding both dystrophin, which binds the intracellular cytoskeleton, and proteins in the extracellular matrix. The DGC is expressed in both cardiac myocytes and vascular smooth muscle but the contributions of each tissue to cardiomyopathy are highly debated. The abnormal glycosylation of dystroglycan leads to a loss of function of dystroglycan as an extracellular matrix receptor and is believed to be responsible for several forms of human muscular dystrophy with associated cardiomyopathy. The overall hypothesis is that the disrupted mechanical link from the cytoskeleton to the extracellular matrix through dystroglycan in cardiac myocytes is the central mechanism directly causing glycosylation-deficient muscular dystrophy associated cardiomyopathy. The specific aims are to: 1) Investigate the primacy of cardiac disruption of dystroglycan, and the relative contributions of skeletal and smooth muscle disruption, to the severity of cardiomyopathy and the mechanical function of the heart. 2) Identify the cell intrinsic mechanisms by which dystroglycan disruption affects muscle cell structure/function in order to identify targets for therapeutic intervention. Glycosylation deficient and dystroglycan gene targeted mice will be used to test the causal and tissue specific role of dystroglycan in cardiomyopathies associated with glycosylation-deficient muscular dystrophies. Experiments in cardiac muscle cells will identify the cell intrinsic mechanisms of myocyte dysfunction that underlie the cardiomyopathy caused by deficiency of functional dystroglycan, and will provide a platform for testing therapeutic interventions aimed at those mechanisms. Because alterations in the DGC are also seen in several other forms of muscular dystrophy and genetic or acquired human cardiomyopathies, this work should contribute broadly to our understanding of human muscular dystrophies and heart disease.