Cardiomyopathy in muscular dystrophies

描述（由申请人提供）：这项工作的长期目标是了解遗传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并设计治疗方法。该建议的重点是与肌营养不良蛋白-糖蛋白复合物（DGC）缺陷相关的肌营养不良症中发生的心肌病。心肌病是一个日益重要的，但研究不足，临床问题的肌营养不良症患者，往往导致过早死亡。肌营养不良聚糖是DGC内的中心跨膜蛋白，结合肌营养不良蛋白（其结合细胞内细胞骨架）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，但每种组织对心肌病的贡献存在高度争议。肌营养不良蛋白聚糖的异常糖基化导致肌营养不良蛋白聚糖作为细胞外基质受体的功能丧失，并被认为是导致几种形式的人肌营养不良症与相关心肌病的原因。总体假设是，心肌细胞中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被破坏是直接引起糖基化缺陷型肌营养不良相关心肌病的中心机制。具体目标是：1）研究肌营养不良蛋白聚糖的心脏破坏的首要性，以及骨骼肌和平滑肌破坏对心肌病严重程度和心脏机械功能的相对贡献。2)确定肌营养不良蛋白聚糖破坏影响肌细胞结构/功能的细胞内在机制，以确定治疗干预的靶点。糖基化缺陷和肌营养不良蛋白聚糖基因靶向小鼠将用于测试肌营养不良蛋白聚糖在与糖基化缺陷型肌营养不良症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肌细胞功能障碍的细胞内在机制，这些机制是由功能性肌营养不良蛋白聚糖缺乏引起的心肌病的基础，并将为测试针对这些机制的治疗干预提供平台。由于DGC的改变也见于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，这项工作应该有助于我们广泛了解人类肌营养不良症和心脏病。

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.