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. .

项目概要： 强直性肌营养不良 (DM1) 是成人和儿童最常见的肌营养不良形式。尽管 还有多种其他多系统效应，DM1主要表现为肌强直和进行性 肌肉萎缩。据报道，肌肉无力、消瘦和疲劳也是最有影响的。 患者的不良后果。 RNA 剪接缺陷已被确定为有毒 RNA 的关键影响 我们和其他人使用来自小鼠和 DM1 患者的成肌细胞，在 DM1 患者中产生 先前证明了有毒RNA对肌原性分化的有害影响。但很少是 了解 DM1 的再生过程或 RNA 毒性对此的影响。解决这个关键问题 如果没有一个模型可以让我们全面了解 RNA 毒性的影响，那么研究就会受到阻碍 关于肌肉再生的研究，以及测试针对这一过程的疗法的研究。卫星细胞是关键的细胞 响应损伤的肌肉再生介质。在这里，我们开发了第一个 RNA 毒性 小鼠模型已证实卫星细胞中有毒 RNA 的表达。我们将使用这个模型来 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 相关的各种关键蛋白（例如 MBNL1 和 CUGBP1）的表达，尤其是 以应对损坏。我们还将使用该模型来研究治疗对卫星细胞的影响 在 RNA 毒性中发挥作用。我们的目标是了解 RNA 毒性在肌肉生长过程中的作用 再生，以便为开发治疗 DM1 型肌营养不良症的疗法提供平台。 。