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?

基本信息

  • 批准号:
    7498990
  • 负责人:
  • 金额:
    $ 1.27万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-06-01 至 2008-08-15
  • 项目状态:
    已结题

项目摘要

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(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症(LGMD)类型的肌肉死亡尚不清楚。对大分子的氧化损伤可导致蛋白质、脂类和核酸的修饰,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,它可能在对抗氧化应激诱导的肌肉损伤方面发挥关键作用。初步研究结果表明,氧化应激在LGMD 11C(缺乏抗肌营养不良蛋白-糖蛋白相关复合蛋白,γ-肌聚糖)小鼠的肌肉死亡中起着重要作用,目前正在进行研究,以调查LGMD II(缺乏质膜修复蛋白,deferlin)小鼠是否存在氧化应激。假设LGMD IIC的初步发现将得到证实,该模型以及LGMD II等其他LGMD模型将存在氧化损伤。此外,还假设抗氧化剂的应用将减少肌肉功能障碍,改善DMD和LGMD肌肉的外观。虽然已经证明细胞凋亡在MDX小鼠的疾病病理中可能没有贡献,但在LGMD中细胞凋亡对疾病病理的贡献仍不清楚。推测抗凋亡因子Bcl2抑制细胞凋亡可改善LGMD模型的肌肉功能和外观。为了验证这些假说,将识别氧化损伤和/或细胞凋亡增加的LGMD模型。下一步,将创建过氧化氢酶过表达的腺相关病毒(AAV)和/或Bcl2过表达的AAV,并在发病前将其传递给幼鼠。对DMD和LGMD的研究将确定增强的过氧化氢酶表达和/或Bcl2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,还将采用体外肌肉功能评估来确定治疗的有效性。预计早期抗氧化剂和/或抗细胞凋亡干预将是有效的治疗策略。肌营养不良是与肌营养不良蛋白-糖蛋白复合体功能障碍有关的肌肉病理的集合,通常是由于缺乏蛋白质所致。根据病理类型,这些患者在十几岁时被轮椅束缚,并在二十岁出头死亡。目前,目前还没有已知的治疗方法,而像这里提出的那些治疗方法受到了肌肉营养不良症社区的欢迎,因为它们减轻了疾病的病理,并最终延长了活动能力和生命。

项目成果

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JOSHUA T SELSBY其他文献

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{{ truncateString('JOSHUA T SELSBY', 18)}}的其他基金

PKR as a therapeutic target for muscular dystrophy
PKR 作为肌营养不良症的治疗靶点
  • 批准号:
    10673733
  • 财政年份:
    2022
  • 资助金额:
    $ 1.27万
  • 项目类别:
PKR as a therapeutic target for muscular dystrophy
PKR 作为肌营养不良症的治疗靶点
  • 批准号:
    10527713
  • 财政年份:
    2022
  • 资助金额:
    $ 1.27万
  • 项目类别:
Internal and External Validation of a Porcine Dystrophinopathy Model
猪肌营养不良症模型的内部和外部验证
  • 批准号:
    10460764
  • 财政年份:
    2021
  • 资助金额:
    $ 1.27万
  • 项目类别:
Characterization of a novel translational model for Becker muscular dystrophy
贝克型肌营养不良症新型转化模型的表征
  • 批准号:
    8583896
  • 财政年份:
    2013
  • 资助金额:
    $ 1.27万
  • 项目类别:
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
  • 财政年份:
    2007
  • 资助金额:
    $ 1.27万
  • 项目类别:

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