Sarcoglycan in Myopathy and Muscle Membrane Stability

描述（由申请人提供）：这是一项研究横纹肌中肌聚糖复合物的更新申请，特别是该复合物在促进肌膜稳定性中的作用。编码肌聚糖亚单位的基因突变产生易受破坏的脆弱肌膜。肌膜破坏是与肌肉和心脏损伤的许多不同病因相关的标志性特征。在原发性肌聚糖基因突变的情况下，对横纹肌、心脏和骨骼肌都有持续的损伤。在骨骼肌中，再生是稳健的，但再生不足以跟上损伤的步伐，最终肌细胞和心肌细胞被纤维化取代，导致虚弱。肌膜不稳定的过程见于肌聚糖基因突变的人，因为肌聚糖是肌营养不良蛋白相关蛋白，所以肌膜不稳定的过程也见于肌营养不良蛋白基因突变的人。这一继续工作的建议是合理的，需要发展的方法来稳定肌膜。这些方法如果成功，有望为肌聚糖基因突变的个体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治疗或预防其他损害肌膜完整性的缺陷的改进方法。在之前的资助期间，我们建议使用无偏见的全基因组方法来映射肌肉萎缩症的修饰符。我们成功地做到了这一点，确定Ltbp 4，潜在的TGF β结合蛋白，作为一种修饰剂的小鼠肌营养不良症。我们通过显示LTBP 4也改变了杜氏肌营养不良症患者的行走来扩展这些发现，突出了这种方法的重要性和相关性。正如所提议的，我们使用超级愈合MRL菌株来鉴定在肌营养不良症小鼠模型中改变肌肉和心脏功能的遗传基因座。我们现在概述实验，以研究候选修饰基因从9号染色体位点，调节肌肉萎缩症的心脏。识别肌营养不良症和心肌病的修饰物指出了我们可以用于预后并最终用于治疗的途径，因为这些途径通过设计可以影响疾病的结果。此外，在上一个资助期间，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γ-肌聚糖。开发和测试这种最小单位的γ-肌聚糖（我们称之为迷你γ）的基本原理是证明使用外显子跳跃作为LGMD 2C治疗的合理性。

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.