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

过氧化氢酶表达是否可以改善 mdx 和 LGMD 小鼠的肌肉功能？

• 批准号: 7274914
• 负责人: JOSHUA T SELSBY
• 金额: $ 4.96万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7274914
• 关键词: Address; Animals; Antioxidants; Apoptosis; Apoptotic; Appearance; Atrophic; Binding; Buffers; Calcium; Cell membrane; Cessation of life; Collection; Communities; Complex; DYSF gene; Data; Dependovirus; Disease; Disease Progression; Duchenne muscular dystrophy; Dystrophin; Enzymes; Etiology; Event; Free Radicals; Functional disorder; Glycoproteins; Goals; Homeostasis; Hydrogen Peroxide; Inflammatory Response; Inhibition of Apoptosis; Intervention; Knock-out; Lead; Life; Limb-Girdle Muscular Dystrophies; Lipids; Literature; Long-Term Effects; Mitochondria; Modeling; Modification; Mus; Muscle; Muscle function; Muscular Dystrophies; Nucleic Acids; Onset of illness; Oxidative Stress; Oxygen; Pathology; Pathway interactions; Patients; Permeability; Phase; Play; Proteins; Role; Sarcoglycans; Signal Transduction; Skeletal system; System; Teenagers; Testing; Therapeutic; Treatment Effectiveness; Water; Wheelchairs; attenuation; catalase; expression vector; gamma Sarcoglycan; improved; improved functioning; killings; macromolecule; mdx mouse; mouse model; prevent; repaired

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.

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肌营养不良症（LGMD）的肌肉死亡仍不清楚。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 11 C（缺乏肌营养不良蛋白-糖蛋白相关复合蛋白，γ肌聚糖）小鼠的肌肉死亡中起重要作用，并且正在进行研究，调查LGMD II（缺乏质膜修复蛋白，dysferlin）小鼠中氧化应激的存在。据推测，LGMD IIC中的初步发现将得到证实，并且氧化损伤将存在于该模型以及LGMD的其他模型（如LGMD II）中。此外，假设抗氧化剂施用将减少肌肉功能障碍并改善DMD和LGMD肌肉的外观。虽然已经证明细胞凋亡可能不会导致mdx小鼠的疾病病理学，但细胞凋亡对LGMD疾病病理学的贡献仍然未知。假设抗凋亡因子Bcl-2抑制细胞凋亡将改善LGMD模型中的肌肉功能和外观。为了检验这些假设，将鉴定具有增加的氧化损伤和/或增加的细胞凋亡的LGMD模型。接下来，将产生过氧化氢酶过表达腺相关病毒（AAV）和/或Bcl-2过表达AAV，并在疾病发作之前将其递送至幼龄小鼠。对DMD和LGMD的研究将确定增强的过氧化氢酶表达和/或Bcl-2表达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，还将采用离体肌肉功能评估来确定治疗的有效性。早期抗氧化和/或抗凋亡干预是有效的治疗策略。肌营养不良症是与肌营养不良蛋白-糖蛋白复合物的功能障碍相关的肌肉病理学的集合，通常是由于蛋白质的缺失。根据病理类型，这些患者在十几岁时被轮椅束缚，在二十出头时死亡。目前，没有已知的治疗方法，如本文提出的治疗方法，受到肌营养不良症社区的欢迎，因为它们减轻了疾病病理学，并最终延长了活动性和寿命。