Calcium and oxidative stress in muscular dystrophy

肌营养不良症中的钙和氧化应激

• 批准号: 8256541
• 负责人: Rainer Ng
• 金额: $ 0.62万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-16 至 2012-06-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8256541
• 关键词: ATP phosphohydrolase; Address; Affect; Aging; Alzheimer' s Disease; Animal Model; Antioxidants; Biological Assay; Breeding; Calcium; Cardiovascular Diseases; Cell Culture Techniques; Cell membrane; Cells; Clinical; Diabetes Mellitus; Disease; Duchenne muscular dystrophy; Dystrophin; Exercise; Exhibits; Fatigue; Fiber; Fluorescence; Functional disorder; Gene Delivery; Generations; Genes; Heart failure; Hereditary Disease; Homeostasis; Individual; Injury; Knock-out; Knockout Mice; Laboratories; Life; Longevity; Mediating; Modeling; Mouse Strains; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle Weakness; Muscle function; Muscular Dystrophies; Newborn Infant; Oxidative Stress; Oxygen; Pathology; Pathway interactions; Patients; Phase; Phenotype; Play; Predisposition; Preparation; Pump; Reactive Oxygen Species; Recombinant adeno-associated virus (rAAV); Relative (related person); Research Personnel; Respiratory Failure; Role; Sarcoplasmic Reticulum; Skeletal Muscle; Superoxide Dismutase; Techniques; Testing; Therapeutic; Therapeutic Effect; Transgenes; Transgenic Mice; Up-Regulation; Utrophin; Viral; Viral Vector; Work; adeno-associated viral vector; base; boys; catalase; gene therapy; improved; interest; mdx mouse; micro-dystrophin; mouse model; muscle degeneration; mutant; overexpression; research study; therapy design

Duchenne muscular dystrophy (DMD) is a lethal genetic disease that affects 1 in 3,500 boys. Accumulating evidence from multiple laboratories corroborate on the involvement of calcium misregulation and oxidative stress as key contributors to the disease, suggesting that upregulation of calcium-sequestering (CaSeq) or anti-oxidant (Antiox) pathways may serve as targets in the treament of DMD. The present application aims to identify the CaSeq/Antiox pathways most significant to the dystrophic phenotype, and assess the therapeutic potential that can be realized by a gene therapy designed to target these pathways. The project is framed by three specific aims and will utilize two murine models of DMD: the mdx and mdx:utrn-/- strains. In Aim 1, muscle cells and isolated muscle preparations will be used characterize the impact of individual CaSeq/Antiox pathways on the dystrophic phenotype. CaSeq/Antiox pathways with the most substantial impact will then be used as targets for viral-mediated gene therapies. To evaluate the efficacy of these gene therapies, dystrophic mice will be injected intravenously with recombinant adeno-associated viruses that contain CaSeq/Antiox transgenes. We will determine whether these transgenes can extend the lifespan of dystrophic mice and correct the pathophyosiology associated with dystrophin-deficiency. Although the scope of the application remains focused on DMD, we expect the therapeutic aspect of our findings to have a direct relevance in the treatment of other diseases where calcium misregulation or oxidative stress play a key role, such as Alzheimer's Disease, aging, diabetes and cardiovascular disease. In the final Aim of the application, we generate mutant mdx mice with modified CaSeq/Antiox pathways by crossing mdx mice with existing strains of mice that possess modified CaSeq/Antiox pathways. These mutant mdx mice will be valuable additions to current dystrophic mouse models, as they allow investigators to isolate the contribution of specific CaSeq/Antiox pathways to the dystrophic phenotype.

Duchenne肌肉营养不良（DMD）是一种致命的遗传疾病，影响3500名男孩中有1个。积累来自多个实验室的证据证实了钙不调节和氧化应激的参与，这是疾病的关键因素，这表明上调钙序列（CASEQ）或抗氧化剂（Antiox）途径可能是DMD障碍的靶标。本应用旨在确定对营养不良表型最重要的CaseQ/Antiox途径，并评估旨在针对这些途径的基因疗法可以实现的治疗潜力。该项目由三个特定的目标构成，并将利用两种DMD的鼠模型：MDX和MDX：UTRN - / - 菌株。在AIM 1中，将使用肌肉细胞和孤立的肌肉制剂，这是单个案例/抗抗病途径对营养不良表型的影响。 CASEQ/ANTIOX途径具有最大的影响，然后将用作病毒介导的基因疗法的靶标。为了评估这些基因疗法的疗效，营养不良小鼠将静脉注射与包含CASEQ/ANTIOX转基因的重组腺相关病毒。我们将确定这些转基因是否可以延长营养不良小鼠的寿命并纠正与肌营养不良蛋白缺乏症相关的病理生物学。尽管该应用程序的范围仍然集中在DMD上，但我们期望我们发现的治疗方面在治疗其他疾病中具有直接相关性，在其他疾病的治疗中，钙失调或氧化应激起着关键作用，例如阿尔茨海默氏病，衰老，糖尿病和心血管疾病。在应用的最终目的中，我们通过将MDX小鼠与具有改良的caseQ/antiox途径的现有小鼠菌株越过MDX小鼠，生成具有改良的CASEQ/ANTIOX途径的突变MDX小鼠。这些突变的MDX小鼠将是当前营养不良小鼠模型的宝贵补充，因为它们允许研究人员隔离特定的CaseQ/Antiox途径对营养不良表型的贡献。