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Elucidating muscle regeneration defects in fukutin KO mice

阐明 fukutin KO 小鼠的肌肉再生缺陷

基本信息

批准号：
8689602
负责人：
Aaron M Beedle
金额：
$ 38.99万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8689602
关键词：
Address Affect Anisotropy Atrophic Basement membrane Binding Biochemical Biochemical Genetics Brain Diseases Career Choice Cell surface Cells Cessation of life Complex Cytoskeleton Data Defect Development Disease Disease Progression Dystroglycan Dystrophin Excision Exposure to Extracellular Matrix Extracellular Matrix Proteins Eye diseases Failure Fiber Functional disorder Genes Genetic Glycoproteins Goals Health Heart Diseases Human Injury Knock-out Knockout Mice Knowledge Life Cycle Stages Link Magnetic Resonance Imaging Mannose Maps Medical Methods Mission Modeling Mus Muscle Muscle Cells Muscle Development Muscle Fibers Muscle Weakness Muscle satellite cell Muscular Dystrophies Mutate Mutation Myoblasts Myofibrils Natural regeneration Nature Neonatal Neuromuscular Diseases Outcome Study Pathway interactions Patients Pharmacy facility Polysaccharides Population Process Proteins Public Health Research Research Support Role Science Signal Transduction Skeletal Muscle Source Stem cells Students Symptoms Technology Teenagers Therapeutic Three-dimensional analysis Time Toxin United States National Institutes of Health Work base burden of illness career cellular targeting college congenital muscular dystrophy design diffusion anisotropy disease phenotype dystroglycanopathy fukutin glycosylation imaging modality improved late disease onset meetings mouse model muscle regeneration novel programs regenerative repaired response satellite cell stem cell niche sugar wasting

项目摘要

DESCRIPTION (provided by applicant): Secondary dystroglycanopathies are a form of muscular dystrophy caused by a failure in the glycosylation (a process of adding sugars) of the protein dystroglycan. Dystroglycan is located at the surface of cells where it tightly binds to extracellular matrix proteins when it is properly glycosylated, forming an important structural and signaling link from the outside to the inside of cells. In secondary dystroglycanopathies, the dystroglycan link outside of cells is disrupted, causing progressive muscle weakness and wasting and possible heart, brain and eye disease. Dystroglycanopathy muscular dystrophies encompass a wide spectrum of disease phenotypes ranging from neonatal onset of severe disease with early death, to late onset disease (teens) with milder symptoms. Mutations in the gene encoding fukutin, FKTN, cause the most common severe form of dystroglycanopathy (Fukuyama congenital muscular dystrophy). Using a novel mouse model of fukutin-dystroglycanopathy, it has recently been shown that dystroglycan abnormalities during muscle development, regeneration and differentiation are required for severe muscular dystrophy in mice. The proposed research aims to address the defects in muscle regeneration following developmental or post-development loss of dystroglycan function. The objectives of the proposed research are to address the role of dystroglycan function in the timing and cell source of muscle regeneration defects using the fukutin-dystroglycanopathy mouse model. To meet these objectives, the proposed specific aims use genetic, histological, biochemical, and imaging methods to track muscle fiber regrowth following muscle injury. This research is directly relevant to human health because abnormalities in muscle regeneration are a key target for developing therapeutics to improve the lives of dystroglycanopathy muscular dystrophy patients. Currently, there is no therapy for dystroglycanopathy muscular dystrophy; therefore, the expected research advances are necessary and relevant to the mission of the NIH.

描述(由申请人提供)：继发性营养不良是一种肌肉营养不良症，由蛋白质营养不良多糖的糖基化(添加糖的过程)失败引起。营养不良多糖位于细胞表面，当适当的糖基化时，它与细胞外基质蛋白紧密结合，形成重要的结构和信号从细胞的外部连接到细胞的内部。在继发性葡萄糖营养不良症中，细胞外的营养不良糖链连接被破坏，导致进行性肌肉无力和消瘦，并可能导致心脏、大脑和眼睛疾病。营养不良症肌营养不良包括广泛的疾病表型，从早逝的新生儿起病，到症状较轻的晚发性疾病(青少年)。编码Fukutin的基因FKTN的突变会导致最常见的严重形式的糖营养不良症(福山先天性肌营养不良症)。利用一种新的Fukutin-dystrocan病小鼠模型，最近的研究表明，在肌肉发育、再生和分化过程中，严重的肌营养不良症需要肌营养不良蛋白聚糖的异常。这项拟议的研究旨在解决发育中或发育后肌营养不良蛋白聚糖功能丧失后肌肉再生方面的缺陷。本研究的目的是利用福库汀-糖营养不良症小鼠模型，探讨肌营养不良蛋白聚糖功能在肌肉再生缺陷发生的时间和细胞来源中的作用。为了达到这些目标，拟议的特定目标使用遗传学、组织学、生化和成像方法来跟踪肌肉损伤后肌肉纤维的再生。这项研究直接关系到人类健康，因为肌肉再生异常是开发治疗方法以改善营养不良症肌营养不良患者生活的关键靶点。目前，还没有治疗糖尿病肌营养不良症的方法，因此，预期的研究进展是必要的，并与美国国立卫生研究院的使命相关。