RNA Toxicity and Muscle Regeneration

RNA 毒性和肌肉再生

• 批准号: 9252112
• 负责人: Mani Subramaniam Mahadevan
• 金额: $ 39.28万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-20 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252112
• 关键词: 3' Untranslated Regions; Address; Adult; Affect; Antibodies; Antisense Oligonucleotides; Caliber; Cell Count; Cell Culture Techniques; Cell Nucleus; Cell physiology; Cells; Child; Collaborations; Defect; Direct Lytic Factors; Embryo; Event; Family; Fatigue; Genes; Goals; Grant; Hand Strength; Histopathology; Immunofluorescence Immunologic; Knockout Mice; Knowledge; Maintenance; Measures; Mediator of activation protein; Modeling; Morbidity - disease rate; Mus; Muscle; Muscle Fatigue; Muscle Weakness; Muscle function; Muscle satellite cell; Muscular Atrophy; Muscular Dystrophies; Myoblasts; Myogenin; Myotonia; Myotonic Dystrophy; Natural regeneration; Patient-Focused Outcomes; Patients; Pharmacologic Substance; Process; Proteins; Quality of life; RNA; RNA Splicing; RNA-Binding Proteins; Regenerative response; Reporting; Reserve Cell; Role; Skeletal Muscle; Symptoms; Tamoxifen; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Tomatoes; Toxic effect; Transcript; Transgenes; Translating; Work; adverse outcome; experimental study; improved; in vivo; mouse model; muscle regeneration; mutant; novel; novel therapeutics; overexpression; receptor; regenerative; repaired; response; satellite cell; self-renewal; success; targeted treatment; therapy development; wasting

Project Summary: Myotonic dystrophy (DM1) is the most common form of muscular dystrophy in adults and children. Though there are a variety of other multi-systemic effects, DM1 is mainly characterized by myotonia and progressive muscle wasting. Muscle weakness, wasting, and fatigue have also been reported as the most impactful adverse outcomes by patients. RNA splicing defects have been identified as key effects of the toxic RNA produced in DM1 patients, and using myoblast cells from mice and DM1 patients, we and others have previously demonstrated the deleterious effects of the toxic RNA on myogenic differentiation. But little is known about the regenerative process in DM1 or the effects of RNA toxicity on this. Addressing this key issue is hampered without a model in which we can develop a thorough understanding of the effects of RNA toxicity on muscle regeneration and one in which to test therapies targeting this process. Satellite cells are key cellular mediators of muscle regeneration in response to damage. Here, we have developed the first RNA toxicity mouse model with demonstrated expression of the toxic RNA in satellite cells. We will use this model to characterize the effects of RNA toxicity on satellite cells and muscle regeneration. We will also study the expression of various key proteins implicated in DM1 such as MBNL1 and CUGBP1 in satellite cells, especially in response to damage. We will also use this model to study the effects of therapeutics on satellite cell function in RNA toxicity. Our goal is to understand the role of RNA toxicity in the process of muscle regeneration in order to provide a platform for developing therapies to treat muscular dystrophy in DM1. .

项目摘要： 肌营养不良症（DM1）是成​​人和儿童中最常见的肌肉营养不良形式。尽管 还有其他多种多系统效应，DM1主要以Myotonia和进步为特征 肌肉浪费。肌肉无力，浪费和疲劳也被报道是最有影响力的 患者的不良结局。 RNA剪接缺陷已被确定为有毒RNA的关键作用 在DM1患者中产生，并使用来自小鼠和DM1患者的成肌细胞，我们和其他人具有 先前证明了有毒RNA对肌源分化的有害作用。但是几乎没有 知道DM1中的再生过程或RNA毒性对此的影响。解决这个关键问题 没有模型受到阻碍 关于肌肉再生以及针对此过程的疗法的一种。卫星细胞是钥匙细胞 肌肉再生的介体响应损害。在这里，我们发展了第一个RNA毒性 小鼠模型在卫星细胞中表现出毒性RNA的表达。我们将使用此模型 表征RNA毒性对卫星细胞和肌肉再生的影响。我们还将研究 卫星细胞中与DM1（例如MBNL1和CUGBP1）中有关的各种关键蛋白的表达，尤其是 响应损坏。我们还将使用该模型研究治疗剂对卫星细胞的影响 RNA毒性的功能。我们的目标是了解RNA毒性在肌肉过程中的作用 再生以提供一个平台来开发DM1中肌营养不良症的疗法。 。