Therapeutic Potent. of e-sarcoglycan in LGMD Type 2D

描述（由申请人提供）：该项目的长期目标是设计一种常染色体隐性肢体-腰带肌营养不良型2D （LGMD-2D）的治疗方法，这种疾病是由于-肌聚糖基因（Sgca）畸变引起的，主要影响肢体和腰带肌肉，导致进行性肌纤维坏死和无力，α -肌聚糖与β -、γ -和δ -肌聚糖相互作用形成亚复合物，增加肌营养不良蛋白-糖蛋白复合物（DGC）的整体稳定性。Epsilon-Sarcoglycan是一种普遍表达的肌肉特异性α - sarcoglycan的同源物，具有43%的同源性和相似的蛋白质结构。Epsilon-Sarcoglycan早在E8.5天就在小鼠胚胎中被检测到表达，而在E15天检测到α -sarcoglycan，初步数据显示，在肌肉再生过程中，Epsilon-Sarcoglycan的表达增加，这表明Epsilon-Sarcoglycan是α -sarcoglycan的胚胎或发育形式。本项目的重点是探索上调epsilon-sarcoglycan水平治疗LGMD-2D的治疗潜力。第一目的假设增加的-肌聚糖表达将取代-肌聚糖在DGC内。对肌肉靶向过表达epsilon-肌聚糖的转基因小鼠的表征将验证这一假设。第二个目标假设增加的肌聚糖表达将补偿异常的α -肌聚糖，以防止肌营养不良的发作。对sgca缺失小鼠过表达epsilon-肌聚糖的分析将验证这一假设。Final Aim假设，在α -肌聚糖缺乏的情况下，增加和持续的epsilon-sarcoglycan表达将防止进一步的肌肉病理和修复原发性膜缺陷，以允许正常的肌肉功能。成年sgca缺失小鼠肌内注射rAAVl epsilon-肌聚糖并进行分析。本项目将研究增加α -肌聚糖水平对预防和治疗α -肌聚糖缺乏症肌萎缩症的功能和生理影响。这些实验的总体结果将揭示增加epsilon-sarcoglycan表达以补偿LGMD-2D患者（-sarcoglycan）的可能性。专注于内源性蛋白如epsilon-sarcoglycan将绕过任何获得性治疗性免疫反应，并为旨在上调epsilon-sarcoglycan的治疗和药物治疗提供新的靶点平台

DESCRIPTION (provided by applicant): The long-term goal of this project is to design a therapy for autosomal recessive limb-girdle muscular dystrophy type 2D (LGMD-2D), which is due to aberrations in the (-sarcoglycan gene (Sgca), and affects mainly limb and girdle muscles to lead to progressive muscle fiber necrosis and weakness, Alpha-Sarcoglycan interacts with beta-, gamma-, and delta-sarcoglycan to form a subcomplex that increases the overall stability of the dystrophin-glycoprotein complex (DGC). Epsilon-Sarcoglycan is a ubiquitously expressed homologue of the muscle-specific alpha- sarcoglycan, sharing 43% identity and a similar protein structure. Epsilon-Sarcoglycan expression is detected as early as day E8.5 in mouse embryos before the detection of alpha-sarcoglycan at E15, and preliminary data shows increased detection during muscle regeneration suggesting that epsilon-sarcoglycan is embryonic or developmental form of alpha-sarcoglycan. This project focuses on exploring the therapeutic potential of upregulating epsilon-sarcoglycan levels for the treatment of LGMD-2D. The First Aim hypothesizes that increased expression of epsilon-sarcoglycan will replace alpha-sarcoglycan within the DGC. Characterization of transgenic mice with targeted overexpression of epsilon-sarcoglycan to muscle will test this hypothesis. The Second Aim hypothesizes that increased expression of epsilon-sarcoglycan will compensate for an aberrant alpha-sarcoglycan to prevent the onset of muscular dystrophy. Analysis of Sgca-null mice overexpressing epsilon-sarcoglycan will test this hypothesis. The Final Aim hypothesizes that increased and sustained epsilon-sarcoglycan expression in alpha-sarcoglycan deficiency will prevent further muscle pathology and repair the primary membrane defect to allow for normal muscle function. Adult Sgca-null mice will be intramuscularly injected with rAAVl epsilon-sarcoglycan and analyzed. This project will investigate the functional and physiological consequences of increased levels of epsilon-sarcoglycan to prevent and treat muscular dystrophy in alpha-sarcoglycan deficiency. The overall results of these experiments will develop the possibility of increased epsilon-sarcoglycan expression to compensate for (-sarcoglycan in LGMD-2D patients. Focusing on an endogenous protein like epsilon-sarcoglycan will bypass any acquired therapeutic immune response, and provides a platform for new targets for therapy and drug treatments aimed at up-regulating epsilon-sarcoglycan