GENE EXPRESSION IN LIMB GIRDLE MUSCULAR DYSTROPHY

描述（由申请人提供）： 肌营养不良症是一组遗传多样的疾病，导致进行性肌肉无力和残疾。近年来，一些基因被发现，当突变时，导致肌肉萎缩症。在人类中，编码肌聚糖蛋白的基因突变产生肢带型肌营养不良症（LGMD）。肌聚糖基因编码蛋白质，每个蛋白质具有单个跨膜结构域。肌聚糖亚基一起在肌营养不良蛋白糖蛋白复合物（DGC）内形成亚复合物。DGC对于稳定细胞骨架、质膜和细胞外基质是重要的。肌聚糖从质膜上的丢失导致骨骼肌和心肌发生变性。肌聚糖基因的功能缺失突变导致肌肉变性和肌膜通透性异常。发现用肌聚糖基因突变改造的小鼠模型靶向肌聚糖功能的不同方面。 缺乏δ-肌聚糖的小鼠对肌肉收缩力的反应增加了肌细胞损伤。相比之下，缺乏γ-肌聚糖的小鼠在响应肌肉收缩时不显示增加的肌细胞损伤，这表明γ-肌聚糖缺乏可能通过非机械或信号传导缺陷引起膜损伤。有趣的是，缺乏γ-肌聚糖或δ-肌聚糖的小鼠的骨骼肌和心肌退化是相同的。因此，这两种不同的小鼠模型修饰了肌聚糖功能的特定机械信号传导方面。我们建议使用γ-肌聚糖和δ-肌聚糖突变体肌肉进行基因表达的微阵列分析，以比较这两种形式的LGMD之间的基因表达变化。肌聚糖突变肌肉中基因表达的变化将与肌营养不良蛋白缺陷肌肉中发现的变化进行比较。最后，我们建议从γ-和δ-肌聚糖突变小鼠的心脏组织中分析基因表达。总之，这些实验将概述这些疾病中出现的基因表达变化的时间概况。

DESCRIPTION (provided by applicant): The muscular dystrophies are a genetically diverse group of disorders that lead to progressive muscle weakness and disability. In recent years, a number of genes have been discovered that, when mutated, lead to muscular dystrophy. In humans, mutations in the genes encoding sarcoglycan proteins produce Limb Girdle Muscular Dystrophy (LGMD). The sarcoglycan genes encode proteins each with a single transmembrane domain. Together, the sarcoglycan subunits form a subcomplex within the dystrophin glycoprotein complex (DGC). The DGC is important for stabilizing the cytoskeleton, the plasma membrane and the extracellular matrix. The loss of sarcoglycan from the plasma membrane causes degeneration to occur in both skeletal and cardiac muscle. Loss of function mutations in sarcoglycan genes causes muscle degeneration and abnormal muscle membrane permeability. Mouse models, engineered with sarcoglycan gene mutations, were found to target different aspects of sarcoglycan function. Mice lacking delta-sarcoglycan develop increased myocyte damage in response to the force of muscle contraction. In contrast, mice lacking gamma-sarcoglycan do not display increased myocyte damage in response to muscle contraction suggesting that gamma-sarcoglycan deficiency may cause membrane damage by a non-mechanical, or signaling, defect. Interestingly, skeletal and cardiac muscle degeneration is identical between mice lacking either gamma-sarcoglycan or delta-sarcoglycan. Therefore, these two different mouse models modify specific mechano signaling aspects of sarcoglycan function. We propose to conduct a microarray analysis of gene expression using gamma-sarcoglycan and delta-sarcoglycan mutant muscle to compare the changes in gene expression between these two forms of LGMD. The changes in gene expression in sarcoglycan mutant muscle will be compared to those found in dystrophin deficient muscle. Finally, we propose to analyze gene expression in cardiac tissue from gamma- and delta-sarcoglycan mutant mice. Together, these experiments will outline the temporal profile of gene expression changes that arise in these disorders.