Sarcoglycan in Myopathy and Muscle Membrane Stability

描述(申请人提供)：营养不良蛋白糖蛋白复合体是一种专门的心肌和骨骼肌复合体。抗肌营养不良蛋白糖蛋白复合体的功能还不完全清楚，但它似乎稳定了骨骼肌和心肌的质膜，并具有机械信号传递能力。在人类患者和小鼠模型中，营养不良蛋白糖蛋白复合体的缺陷都会导致骨骼肌营养不良和心肌病。我们之前设计了缺乏伽马-肌聚糖或三角洲-肌聚糖的小鼠模型，发现这些小鼠有效地模拟了人类的疾病。在小鼠中，就像在患有营养不良蛋白-糖蛋白复合体基因缺陷的人类中一样，表型结果存在差异。我们假设这种表型变异的某些方面是受基因控制的。 我们现在建议识别新的基因，并测试现有基因从肌聚糖基因突变中调节表型的能力。我们现在表明，遗传背景会影响肌营养不良症的两种不同的数量特征。纤维化度和膜通透性的程度都与特定的遗传背景有关。我们建议定位这些数量性状，以确定影响肌营养不良症表型结果的遗传修饰基因座。遗传修饰基因是有用的，因为它们可以帮助咨询患有肌营养不良症的对象，并导致新的治疗途径。我们将研究更多的遗传背景，以了解它们抑制伽马肌糖缺失小鼠的肌营养不良和心肌病表型的能力。我们现在表明，骨骼肌主要整合素复合体的缺陷会导致严重的肌营养不良表型，骨骼肌退化和早期致死性增强。因此，我们将研究整合素作为肌营养不良表型修饰剂的细胞和分子效应。最后，将利用遗传学和药理学方法研究内皮型一氧化氮合酶作为肢体带状肌营养不良症心肌病特征的修饰物。这些发现将提高我们对肌营养不良和心肌病中细胞缺陷的理解，并可能有助于设计新的治疗策略。

DESCRIPTION (provided by applicant): The dystrophin glycoprotein complex is a specialized complex of cardiac and skeletal muscle. The function of the dystrophin glycoprotein complex is not fully understood, but it appears to stabilize the plasma membrane of skeletal and cardiac muscle and serve in a mechanosignaling capacity. Defects in the dystrophin glycoprotein complex lead to skeletal muscle dystrophy and cardiomyopathy in both human patients and mouse models. We previously engineered mouse models lacking gamma-sarcoglycan or delta-sarcoglycan and found that these mice effectively model the human disorder. In mice, as in humans with dystrophin-glycoprotein complex gene defects, there is variability in the phenotypic outcome. We hypothesize that aspects of this phenotypic variability is under genetic control. We now propose to identify new genes and to test existing genes for their ability to modulate the phenotype from sarcoglycan gene mutations. We now show that the genetic background influences two different quantitative features of muscular dystrophy. The degree of fibrosis and the degree of membrane permeability both significantly vary in gamma sarcoglycan null mice related to the specific genetic background. We propose to map these quantitative traits to determine the genetic modifier loci that affect the phenotypic outcome in muscular dystrophy. Genetic modifier genes are useful since they may aid in counseling subjects with muscular dystrophy as well as lead to new avenues of therapy. We will study to additional genetic backgrounds for their ability to suppress the muscular dystrophy and cardiomyopathy phenotypes in gamma sarcoglycan null mice. We show now that defects in the major integrin complex of skeletal muscle lead to a profound muscular dystrophy phenotype with enhanced skeletal muscle degeneration and early lethality. Therefore, we will investigate the cellular and molecular effects of integrin as a modifier of the muscular dystrophy phenotype. Lastly, endothelial nitric oxide synthase will be studied as a modifier of the cardiomyopathic features of limb girdle muscular dystrophy using genetic and pharmacologic approaches. These findings will improve our understanding of the cellular defects in muscular dystrophy and cardiomyopathy and may help devise new strategies for therapy.