RNA Toxicity and Muscle Regeneration

RNA 毒性和肌肉再生

基本信息

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
项目类别：
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&apos 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

项目摘要

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。。