Sarcoglycan in Myopathy and Muscle Membrane Stability

描述（由申请人提供）：肌营养不良蛋白糖蛋白复合物是心肌和骨骼肌的一种特殊复合物。肌营养不良蛋白糖蛋白复合物的功能尚未完全了解，但它似乎稳定骨骼肌和心肌的质膜，并在机械信号传导能力。肌营养不良蛋白糖蛋白复合物的缺陷导致人类患者和小鼠模型中的骨骼肌营养不良和心肌病。我们之前设计了缺乏γ-肌聚糖或δ-肌聚糖的小鼠模型，发现这些小鼠有效地模拟了人类疾病。在小鼠中，如同在患有肌营养不良蛋白-糖蛋白复合物基因缺陷的人类中一样，表型结果存在变异性。我们假设，这种表型变异的各个方面是在遗传控制下。 我们现在建议确定新的基因，并测试现有基因的能力，以调节表型的肌聚糖基因突变。我们现在表明，遗传背景影响肌营养不良症的两个不同的定量特征。纤维化程度和膜通透性的程度都显着不同的γ-肌聚糖裸小鼠相关的特定遗传背景。我们建议映射这些数量性状，以确定影响肌营养不良症的表型结果的遗传修饰基因位点。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受试者，并导致新的治疗途径。我们将研究额外的遗传背景，以抑制γ-肌聚糖缺失小鼠的肌营养不良和心肌病表型。我们现在表明，骨骼肌的主要整合素复合物的缺陷导致严重的肌营养不良症表型，增强骨骼肌变性和早期致死性。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，内皮型一氧化氮合酶将被研究作为一个修改器的肢带型肌营养不良症的心肌病变特征，使用遗传和药理学的方法。这些发现将提高我们对肌营养不良症和心肌病细胞缺陷的理解，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.