Cardiomyopathy in muscular dystrophies

肌营养不良症中的心肌病

• 批准号: 7144634
• 负责人: Daniel E Michele
• 金额: $ 33.32万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7144634
• 关键词: Adenoviridae; cardiac myocytes; cellular pathology; cytoskeleton; dystrophin; extracellular matrix; extracellular matrix proteins; gene targeting; genetic disorder; genetically modified animals; glycoproteins; glycosylation; hypertrophic myocardiopathy; laboratory mouse; mechanical stress; membrane proteins; muscular dystrophy; protein binding; protein structure function; smooth muscle; striated muscles; tissue /cell culture; transfection /expression vector

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.

描述（由申请人提供）：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，以便阐明常见机制并设计人类心血管疾病的治疗方法。该提案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。心肌病是肌营养不良症患者中一个日益重要但尚未得到充分研究的临床问题，常常导致过早死亡。肌营养不良聚糖是 DGC 内的中央跨膜蛋白，结合肌营养不良蛋白（与细胞内细胞骨架结合）和细胞外基质中的蛋白质。 DGC 在心肌细胞和血管平滑肌中表达，但每种组织对心肌病的贡献存在激烈争议。肌营养不良聚糖的异常糖基化导致肌营养不良聚糖作为细胞外基质受体的功能丧失，并被认为是导致多种形式的人类肌营养不良症及相关心肌病的原因。总体假设是，心肌细胞中通过肌营养不良聚糖从细胞骨架到细胞外基质的机械连接被破坏，是直接导致糖基化缺陷型肌营养不良症相关心肌病的核心机制。具体目标是： 1) 研究肌营养不良聚糖对心脏破坏的首要作用，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影响。 2) 确定肌营养不良聚糖破坏影响肌肉细胞结构/功能的细胞内在机制，以确定治疗干预的目标。糖基化缺陷和肌营养不良症基因靶向小鼠将用于测试肌营养不良症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。心肌细胞实验将确定肌细胞功能障碍的细胞内在机制，该机制是功能性肌营养不良聚糖缺乏引起的心肌病的基础，并将提供一个平台来测试针对这些机制的治疗干预措施。由于 DGC 的改变也见于其他几种形式的肌营养不良症以及遗传性或获得性人类心肌病，因此这项工作应该广泛有助于我们对人类肌营养不良症和心脏病的理解。