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，以便揭示人类心血管疾病的共同机制和设计治疗方法。本提案的重点是发生在与肌营养不良蛋白-糖蛋白复合物（DGC）缺陷相关的肌营养不良患者的心肌病。心肌病是肌营养不良患者的一个日益重要但研究不足的临床问题，经常导致过早死亡。肌营养不良聚糖是DGC内的中心跨膜蛋白，结合与细胞内细胞骨架结合的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均有表达，但这两种组织对心肌病的影响存在高度争议。糖异常糖基化导致糖异常作为细胞外基质受体的功能丧失，并被认为是几种形式的人类肌营养不良伴心肌病的原因。总的假设是，从细胞骨架到细胞外基质通过心肌细胞的糖代谢异常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中心机制。具体目的是：1)研究糖酐异常引起心脏损伤的首要原因，以及骨骼肌和平滑肌损伤对心肌病严重程度和心脏机械功能的相对影响。2)确定三聚糖障碍破坏影响肌肉细胞结构/功能的细胞内在机制，以确定治疗干预的靶点。糖基化缺陷和糖异常蛋白基因靶向小鼠将被用来测试糖异常蛋白在与糖基化缺陷型肌营养不良相关的心肌病中的因果关系和组织特异性作用。心肌细胞的实验将确定心肌细胞功能障碍的细胞内在机制，这些机制是由功能性糖代谢障碍缺乏引起的心肌病的基础，并将为针对这些机制的治疗干预测试提供一个平台。由于DGC的改变也见于其他几种形式的肌肉萎缩症和遗传性或获得性人类心肌病，因此这项工作将广泛有助于我们对人类肌肉萎缩症和心脏病的理解。

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.