Sarcoglycan in Myopathy and Muscle Membrane Stability

描述(申请人提供)：这是一份续展申请，旨在研究横纹肌中的肌聚糖复合体，特别是该复合体在促进肌膜稳定性方面的作用。编码肌聚糖亚单位的基因突变会产生一种脆弱的肌膜，容易受到破坏。肌膜破坏是肌肉和心脏损伤的许多不同病因相关的显著特征。在初级肌糖基因突变的情况下，横纹肌，包括心脏和骨骼肌，都会受到持续的损伤。在再生旺盛的骨骼肌中，没有足够的再生来跟上损伤的步伐，最终会有心肌细胞和心肌细胞被纤维化取代，导致虚弱。肌糖蛋白基因突变的人和肌营养不良蛋白基因突变的人一样，可以看到肌膜不稳定的过程，因为肌糖蛋白是肌营养不良蛋白相关的蛋白。这项继续工作的建议是合理的，因为需要开发稳定肌膜的方法。这种方法，如果成功，有望为患有肌聚糖基因突变的个人提供潜在的治疗方法。重要的是，了解稳定心脏和肌肉肌膜的机制也可能产生更好的治疗或预防其他损害肌膜完整性的缺陷的方法。在之前的资助阶段，我们建议使用一种无偏见的全基因组方法来定位肌营养不良症的修饰基因。我们成功地做到了这一点，确定了潜在的转化生长因子β结合蛋白Ltbp4作为小鼠肌营养不良症的修饰物。我们扩展了这些发现，显示LTBP4也改善了Duchenne肌营养不良症的行走，强调了这一方法的重要性和相关性。正如所建议的，我们使用超愈MRL品系来确定在肌营养不良症小鼠模型中改变肌肉和心脏功能的基因位点。我们现在概述研究9号染色体的候选修饰基因的实验，该基因在肌营养不良症中调节心脏。识别肌营养不良和心肌病的修饰物指出了我们可以用来预测预后并最终用于治疗的途径，因为这些途径经过设计可以影响疾病的结果。此外，在之前的资助期间，我们开发了重要的初步数据，确定了足以改善肌肉和心脏功能的最小单位的伽马-肌聚糖。开发和测试这种最小单位的伽马-肌聚糖，我们称之为迷你伽马，其基本原理是证明使用外显子跳过作为治疗LGMD2C的方法是合理的。

DESCRIPTION (provided by applicant): This is a renewal application to study the sarcoglycan complex in striated muscle, and specifically the role of this complex in promoting sarcolemmal stability. Mutations in the genes encoding the sarcoglycan subunits produce a fragile sarcolemma that is susceptible to disruption. Sarcolemmal disruption is a hallmark feature associated with many different etiologies of muscle and heart injury. In the case of primary sarcoglycan gene mutations, there is ongoing injury to striated muscle, both heart and skeletal muscle. In skeletal muscle, where regeneration is robust, there is insufficient regeneration to keep pace with injury, and ultimately there is replacement of myocytes and cardiomyocytes by fibrosis, leading to weakness. The process of sarcolemmal instability is seen in humans with sarcoglycan gene mutations, as it is in those with dystrophin gene mutations, since the sarcoglycans are dystrophin-associated proteins. This proposal for continued work is justified by the need to develop approaches to stabilize the sarcolemma. Such approaches, if successful, are expected to provide a potential therapeutic for individuals with sarcoglycan gene mutation. Importantly, understanding mechanisms to stabilize the sarcolemma of heart and muscle could also potential yield improved approaches towards treating or preventing other defects that compromise sarcolemmal integrity. In the prior funding period, we proposed to use an unbiased genomewide approach to map modifiers of muscular dystrophy. We successfully did this, identifying Ltbp4, the latent TGFbeta binding protein, as a modifier for murine muscular dystrophy. We extended these findings by showing that LTBP4 also modifies walking in Duchenne Muscular Dystrophy, highlighting the importance and relevance of this approach. As proposed, we used the superhealing MRL strain to identify genetic loci that modify muscle and heart function in mouse models of muscular dystrophy. We now outline experiments to study candidate modifier genes from a chromosome 9 locus that regulates the heart in muscular dystrophy. Identifying modifiers for muscular dystrophy and cardiomyopathy points to pathways that we can exploit for prognosis and ultimately for therapy since these pathways, by design, can influence the outcome of disease. Additionally, during the prior funding period, we developed significant preliminary data identifying a minimal unit of gamma-sarcoglycan that is sufficient to improve muscle and heart function. The rationale for developing and testing this minimal unit of gamma- sarcoglycan, which we termed mini-gamma, is to justify the use of exon skipping as a treatment for LGMD2C.