RNA Toxicity and Muscle Regeneration

项目概要： 强直性肌营养不良（DM1）是成人和儿童中最常见的肌营养不良形式。虽然 DM1还存在多种其他多系统效应，主要表现为肌强直和进行性 肌肉萎缩据报道，肌肉无力、消瘦和疲劳也是最具影响力的 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， 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 先前证实了毒性RNA对肌原性分化的有害作用。但很少有人 已知DM1的再生过程或RNA毒性对此的影响。解决这一关键问题 如果没有一个模型，我们可以发展一个彻底的理解RNA毒性的影响， 一个是研究肌肉再生，另一个是测试针对这一过程的疗法。卫星细胞是关键的细胞 肌肉再生的介质，以应对损害。在这里，我们已经开发出第一个RNA毒性 小鼠模型，证明卫星细胞中有毒RNA的表达。我们将利用这一模式， 表征RNA毒性对卫星细胞和肌肉再生的影响。我们亦会研究 DM1中涉及的各种关键蛋白如MBNL1和CUGBP1在卫星细胞中的表达，特别是 以应对损害。我们也将利用这个模型来研究治疗对卫星细胞的影响， 在RNA毒性中起作用。我们的目标是了解RNA毒性在肌肉损伤过程中的作用。 再生，以便为开发治疗DM 1中的肌营养不良症的疗法提供平台。 .

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. .