Calcium and oxidative stress in muscular dystrophy

肌营养不良症中的钙和氧化应激

• 批准号: 8064686
• 负责人: Rainer Ng
• 金额: $ 5.3万
• 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 2013-04-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8064686
• 关键词: Address; Affect; Aging; Alzheimer' s Disease; Animal Model; Antioxidants; Biological Assay; Breeding; Ca(2+)-Transporting ATPase; 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; public health relevance; research study; therapy design

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Duchenne muscular dystrophy is a lethal genetic disease that affects 1 in 3,500 boys. Calcium and oxygen molecules affect these diseased muscles in many ways, most of which are not well understood. This project will first study how calcium and oxygen molecules interact within muscle cells, and then subsequently examine whether controlling these molecules can be an effective way to treat this disease.

描述（由申请人提供）：杜氏肌营养不良症 (DMD) 是一种致命的遗传性疾病，每 3,500 名男孩中就有 1 人受到影响。来自多个实验室的越来越多的证据证实钙失调和氧化应激是该疾病的关键因素，表明钙螯合 (CaSeq) 或抗氧化 (Antiox) 途径的上调可能作为 DMD 治疗的目标。本申请旨在鉴定对营养不良表型最重要的CaSeq/Antiox途径，并评估针对这些途径设计的基因疗法可以实现的治疗潜力。该项目由三个具体目标构成，并将利用两种 DMD 小鼠模型：mdx 和 mdx:utrn-/- 菌株。在目标 1 中，将使用肌肉细胞和分离的肌肉制剂来表征单个 CaSeq/Antiox 途径对营养不良表型的影响。具有最重大影响的 CaSeq/Antiox 途径将被用作病毒介导的基因治疗的靶标。为了评估这些基因疗法的功效，营养不良小鼠将被静脉注射含有 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相关的病理生理学。尽管该应用的范围仍然集中在 DMD 上，但我们预计我们的研究结果的治疗方面与钙失调或氧化应激起关键作用的其他疾病的治疗有直接相关性，例如阿尔茨海默病、衰老、糖尿病和心血管疾病。在该申请的最终目标中，我们通过将 mdx 小鼠与具有修饰的 CaSeq/Antiox 途径的现有小鼠品系杂交，产生具有修饰的 CaSeq/Antiox 途径的突变 mdx 小鼠。这些突变 mdx 小鼠将为当前营养不良小鼠模型提供有价值的补充，因为它们使研究人员能够分离出特定 CaSeq/Antiox 途径对营养不良表型的贡献。 公众健康相关性：杜氏肌营养不良症是一种致命的遗传性疾病，每 3,500 名男孩中就有 1 人受到影响。钙和氧分子以多种方式影响这些患病的肌肉，其中大部分尚不清楚。该项目将首先研究钙和氧分子在肌肉细胞内如何相互作用，然后研究控制这些分子是否可以成为治疗这种疾病的有效方法。