RNA Toxicity and Muscle Regeneration

项目总结： 强直性肌营养不良症(DM1)是成人和儿童中最常见的肌营养不良症。尽管 还有其他多种多系统效应，DM1主要以肌强直和进行性为特征 肌肉萎缩。据报道，肌肉无力、消瘦和疲劳也是影响最大的 患者的不良后果。RNA剪接缺陷已被确定为有毒RNA的关键影响因素 通过使用来自小鼠和DM1患者的成肌细胞，我们和其他人已经 以前证明了有毒的RNA对肌源性分化的有害影响。但很少是这样 了解DM1中的再生过程或RNA毒性对此的影响。解决这一关键问题 如果没有一个模型，我们可以彻底了解RNA毒性的影响，就会受到阻碍 关于肌肉再生和测试针对这一过程的治疗方法。卫星细胞是关键的细胞 肌肉再生的中介物对损伤的反应。在这里，我们已经开发出第一个RNA毒性 小鼠模型，证实了卫星细胞中有毒RNA的表达。我们将使用此模型来 描述RNA毒性对卫星细胞和肌肉再生的影响。我们亦会研究 与DM1相关的多种关键蛋白如MBNL1和CUGBP1在卫星细胞中的表达 作为对损害的反应。我们还将利用这个模型来研究治疗对卫星细胞的影响。 在RNA毒性中的作用。我们的目标是了解rna毒性在肌肉过程中的作用。 再生，为开发治疗DM1肌营养不良症的治疗方法提供平台。 。

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. .