Sarcoglycan in Myopathy and Muscle Membrane Stability

项目摘要 肌聚糖复合物稳定肌肉的质膜，并且编码肌聚糖的基因突变。 肌聚糖亚单位产生脆弱的肌膜。肌膜破坏是骨骼肌的一个普遍特征， 和心肌损伤，以及由肌营养不良蛋白或肌聚糖基因引起的肌病疾病 突变。这项研究计划的主要目标是了解肌营养不良蛋白 和肌聚糖稳定肌膜，并鉴定肌营养不良症的遗传修饰剂。因为 我们假设这些罕见的遗传性疾病与肌肉损伤（包括心肌损伤）有共同的特征， 肌聚糖突变的修饰剂不仅对肌营养不良蛋白病有类似的作用， 一般来说，肌肉损伤。我们使用肌聚糖病的小鼠模型Sgcg 缺乏γ-肌聚糖的模型。选择这个模型是因为有强有力的证据表明， 肌聚糖基因突变的人类修饰剂。我们在Sgcg小鼠中使用了交叉策略， 在129遗传背景和严重表型中看到的轻度保护表型的优势 在有害DBA背景下的Sgcg小鼠中观察到。我们成功鉴定了多种基因修饰剂 包括潜伏性TGFβ结合蛋白4（LTBP 4）和膜联蛋白A6（ANXA 6）。两种修饰基因都是 生物学上与损伤修复和恢复相关，并验证该方法的实用性。与此同时， 进展，在开发和批准反义寡核苷酸介导的外显子 跳绳作为杜氏肌营养不良症的治疗方法我们开发了一种类似的方法来治疗肢体 带状肌营养不良症（LGMD）2C，是由γ-肌聚糖基因引起的肌营养不良症 突变。在支持的最后一个阶段，我们展示了外显子跳跃在由 多名LGMD 2C突变患者，表明Mini-gamma，即小的内部缺失形式， γ-肌聚糖稳定肌膜。我们现在将集中于将外显子跳跃与 修饰剂方法以引起遗传校正并促进肌膜稳定性。我们将开发临床前 支持外显子跳跃的数据，同时证明了关于基因突变的关键生物学机制。 肌膜稳定性与肌肉生长的关系。

PROJECT SUMMARY The sarcoglycan complex stabilizes the plasma membrane of muscle, and mutations in the genes encoding sarcoglycan subunits produce a fragile sarcolemma. Sarcolemmal disruption is a general feature of skeletal and cardiac muscle injury, as well as the myopathic disorders arising from dystrophin or sarcoglycan gene mutations. This research program has as its primary goal to understand the mechanisms by which dystrophin and sarcoglycan stabilize the sarcolemma and to identify genetic modifiers of muscular dystrophy. Because these rare genetic disorders share features with muscle injury, including cardiac muscle injury, we hypothesize that modifiers of sarcoglycan mutations will not only exert as similar effect on dystrophinopathies but also on muscle injury in general. We mapped genetic modifiers using a mouse model of sarcoglycanopathy, the Sgcg model which lacks gamma-sarcoglycan. This model was selected because there was strong evidence for modifiers in humans with sarcoglycan gene mutations. We used an intercross strategy in Sgcg mice, taking advantage of the mild protective phenotype seen in the 129 genetic background and the severe phenotype seen in Sgcg mice on the deleterious DBA background. We successfully identified multiple genetic modifiers including latent TGFβ binding protein 4 (LTBP4) and annexin A6 (ANXA6). Both modifier genes are biologically linked to injury repair and recovery and validate the utility of the method. Concomitant with this progress, there have advances in the development and approval of antisense oligonucleotide-mediated exon skipping as a therapy for Duchenne Muscular Dystrophy. We developed a similar approach to treat Limb Girdle Muscular Dystrophy (LGMD) 2C, which is the form of muscular dystrophy from γ-sarcoglycan gene mutations. In the last period of support, we showed the feasibility of exon skipping in cell lines generated from multiple patients with LGMD 2C mutations, demonstrating that Mini-gamma, the small internally deleted form of gamma-sarcoglycan stabilizes the sarcolemma. We will now focus on combining exon skipping together with modifier approaches to elicit genetic correction and promote sarcolemmal stability. We will develop preclinical data to support exon skipping and simultaneously demonstrate key biological mechanisms about the relationship between sarcolemmal stability and muscle growth.