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遗传定义的遗传性心肌病的机制，以阐明人类心血管疾病的常见机制并设计疗法。该建议的重点是与肌营养不良蛋白 - 糖蛋白复合物（DGC）缺陷相关的肌肉营养不良中发生的心肌病。心肌病在肌肉营养不良患者中越来越重大但已研究，临床问题经常导致过早死亡。 Dystroglycan是DGC内的中央跨膜蛋白，结合了肌营养不良蛋白，它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均表达，但每种组织对心肌病的贡献都高度争议。多糖糖的异常糖基化导致dystroglycan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与相关心肌病的人类肌肉营养不良的形式。总体假设是，从细胞骨架到心肌细胞中的肌骨骼到细胞外基质的破坏机械联系是直接导致糖基化缺陷肌肉营养不良的心脏营养不良相关的心肌病的中心机制。具体目的是：1）研究多糖果心脏破坏的首要性，以及骨骼和平滑肌破坏对心肌病的严重程度和心脏的机械功能的相对贡献。 2）确定细胞固有机制，通过这些机制，肌肉干扰会影响肌肉细胞结构/功能，以确定治疗干预的靶标。糖基化缺陷和多糖基因靶向小鼠将用于测试多糖糖在与糖基化缺陷型肌肉营养不良相关的心肌病中的因果和组织特异性作用。心肌细胞中的实验将确定肌细胞功能障碍的固有机制，这些机制是由于功能性障碍性肿瘤不足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措施提供平台。由于DGC的改变也可以在其他几种形式的肌肉营养不良和遗传或获得性的人类心肌病中看到，因此这项工作应广泛地有助于我们对人类肌肉营养不良和心脏病的理解。