Does catalase expression improve the function muscles from of mdx and LGMD mice?

描述（由申请人提供）：肌营养不良蛋白缺陷型骨骼肌（DMD）对氧化损伤高度敏感，然而，氧化应激是否导致非肌营养不良蛋白缺陷型（LGMD）的肌肉死亡尚不清楚。对大分子的氧化损伤可导致蛋白质、脂质和核酸的修饰，从而导致细胞功能障碍和死亡。过氧化氢酶是一种将过氧化氢转化为水和氧气的抗氧化酶，可能在对抗氧化应激引起的肌肉损伤中发挥关键作用。初步研究结果表明，氧化应激在LGMD 11C（缺乏肌营养不良蛋白-糖蛋白相关复合物蛋白，γ肌聚糖）小鼠的肌肉死亡中起重要作用，目前正在研究LGMD II（缺乏质膜修复蛋白，异铁蛋白）小鼠中氧化应激的存在。假设LGMD IIC的初步研究结果将得到证实，该模型以及LGMD II等其他LGMD模型将存在氧化损伤。此外，据推测，抗氧化管理将减少肌肉功能障碍，改善DMD和LGMD肌肉的外观。虽然已经证明mdx小鼠的细胞凋亡可能与疾病病理无关，但在LGMD中细胞凋亡对疾病病理的贡献仍然未知。我们推测抗凋亡因子Bcl-2抑制细胞凋亡可以改善LGMD模型的肌肉功能和外观。为了验证这些假设，将确定具有增加氧化损伤和/或增加细胞凋亡的LGMD模型。接下来，创建过氧化氢酶过表达的腺相关病毒（AAV）和/或Bcl-2过表达的AAV，并在发病前将其传递给年轻小鼠。DMD和LGMD的研究将确定过氧化氢酶表达和/或Bcl-2表达的增强是否可以减缓营养不良病理的进展。除了详细的组织学检查外，还将评估离体肌肉功能以确定治疗的有效性。预计早期抗氧化和/或抗凋亡干预将是有效的治疗策略。肌营养不良症是与肌营养不良蛋白-糖蛋白复合物功能障碍有关的肌肉病理的集合，通常是由于蛋白质缺失引起的。根据不同的病理类型，这些患者在十几岁时就被轮椅束缚住了，在二十岁出头就去世了。目前，尚无已知的治愈方法，而这些治疗方法，如本文提出的，受到肌肉萎缩症社区的欢迎，因为它们可以减轻疾病病理，最终延长活动能力和寿命。

DESCRIPTION (provided by applicant): Dystrophin-deficient skeletal (DMD) muscle is highly susceptible to oxidative damage, however, it remains unknown whether oxidative stress contributes to muscle death in non-dystrophin-deficient types of muscular dystrophies (LGMD). Oxidative damage to macromolecules can lead to modification to proteins, lipids, and nucleic acids resulting in cellular dysfunction and death. Catalase, an antioxidant enzyme that converts hydrogen peroxide into water and oxygen, may play a key role in counteracting oxidative stress-induced muscle damage. Preliminary findings suggest that oxidative stress plays a significant role in muscle death in LGMD 11C (lack dystrophin-glycoprotein associated complex protein, gamma sarcoglycan) mice and studies are ongoing investigating the presence of oxidative stress in LGMD II (lack plasma membrane repair protein, dysferlin) mice. It is hypothesized that preliminary findings in LGMD IIC will be confirmed and oxidative damage will be present in this model as well as other models of LGMD such as LGMD II. Further, it is hypothesized that anti-oxidant administration will reduce muscle dysfunction and improve the appearance of both DMD and LGMD muscle. While it has been demonstrated that apoptosis likely does not contribute to disease pathology in the mdx mouse, the contribution of apoptosis to disease pathology in LGMD remains unknown. It is hypothesized that inhibition of apoptosis by anti-apoptotic factor Bcl-2 will improve muscle function and appearance in models of LGMD. To test these hypotheses, models of LGMD that have increased oxidative damage and/or increased apoptosis will be identified. Next, a catalase over- expression adeno-associated virus (AAV) and/or Bcl-2 over-expression AAV will be created and delivered to young mice prior to disease onset. Studies in both DMD and LGMD will determine if enhanced catalase expression and/or Bcl-2 expression can slow progression of dystrophic pathology. In addition to a detailed histological examination, an assessment of ex vivo muscle function will also be employed to determine the effectiveness of treatments. It is anticipated that early anti-oxidant and/or anti-apoptotic intervention will be effective therapeutic strategies. The muscular dystrophies are a collection of muscle pathologies related to dysfunction of the dystrophin- glycoprotein complex, usually due to an absent protein. Depending on the pathology type, these patients are wheel chair bound by the early teens and die in the early twenties. Currently, no known cure is available and therapies, such as those proposed here, are welcomed by the muscular dystrophy community as they alleviate disease pathology and ultimately prolong mobility and life.