Costamere Defects in Muscular Dystrophies

肌营养不良症中的肋部缺陷

• 批准号: 6870890
• 负责人: JAMES M ERVASTI
• 金额: $ 31.97万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6870890
• 关键词: actins; affinity chromatography; biological signal transduction; cellular pathology; disease /disorder etiology; dystrophin; gene expression; gene mutation; gene targeting; genetically modified animals; laboratory mouse; mass spectrometry; microfilaments; molecular assembly /self assembly; molecular pathology; muscle cells; muscle contraction; muscle proteins; muscular dystrophy; phenotype; protein protein interaction; protein structure function; sarcolemma; striated muscles; western blottings

DESCRIPTION (provided by applicant): Costameres are subsarcolemmal protein assemblies in striated muscle cells that circumferentially align in register with the Z disk of peripheral myofibrils and physically couple force-generating sarcomeres with the sarcolemma. Costameres are clearly important for normal muscle function because several constituent proteins are the primary sites of defect in human muscular dystrophies and dilated cardiomyopathies. We previously demonstrated that dystrophin, the product of the gene defective in Duchenne and Becker muscular dystrophies, forms an important mechanical link between costameric y-actin filaments and the sarcolemma. Our preliminary data indicates that y-actin protein levels are dramatically increased in dystrophin-deficient muscle. While an increase in the y-actin monomer pool likely stabilizes costameric filaments by mass action, excess myoplasmic y-actin may have adverse consequences for muscle cell function. The major objective of this project is to elucidate the pathogenic mechanisms linking dystrophin gene defects to muscular dystrophy phenotypes. In this proposal, we will test the novel hypotheses that increased y-actin may directly alter the activity of other muscle cell constituents involved in signaling, gene expression, or contractility. We will characterize new transgenic mouse lines to determine which dystrophy phenotypes may be caused by increased myoplasmic y-actin concentration in the absence of sarcolemmal damage. Finally, we will assess the role of y-actin in costamere assembly and mechanical function by characterizing new lines of mice where it is specifically ablated in striated muscle. The proposed research will directly address the role of increased y-actin expression and costamere instability in causing the skeletal muscle pathologies associated with dystrophinopathy.

描述（由申请人提供）：COSTAMERES是横纹肌肉细胞中的亚芳族蛋白质组件，它们在寄存器中与周围肌纤维的Z磁盘呈圆周排列，并在物理上与肉眼相结合。 Costameres对于正常的肌肉功能显然很重要，因为几种组成蛋白是人类肌肉营养不良和扩张心肌病的主要缺陷部位。我们先前证明了肌营养不良蛋白是Duchenne和Becker肌肉营养不良的基因缺陷的产物，在Costameric Y-肌动蛋白丝和肌膜上形成了重要的机械联系。我们的初步数据表明，肌营养不良蛋白缺乏肌肉的Y-肌动蛋白水平急剧增加。虽然Y-肌动蛋白单体池的增加可能会通过质量作用稳定costameric丝，但过量的肌瘤Y-肌动蛋白可能会对肌肉细胞功能产生不利的后果。该项目的主要目的是阐明将肌营养不良蛋白缺陷与肌肉营养不良表型联系起来的致病机制。在此提案中，我们将测试增加Y-肌动蛋白可能直接改变其他肌肉细胞成分参与信号传导，基因表达或收缩力的活性的新假设。我们将表征新的转基因小鼠系，以确定哪些营养不良表型可能是由于没有肌膜损伤的情况下增加的肌瘤Y-肌动蛋白浓度引起的。最后，我们将通过表征新的小鼠在横纹肌肉中逐渐消融的新小鼠来评估Y-肌动蛋白在Costamere组装和机械功能中的作用。拟议的研究将直接解决Y-肌动蛋白表达增加和COSTAMERE不稳定在引起与肌营养不良症相关的骨骼肌病理学方面的作用。