Disease Progression in Myotonic Dystrophy

强直性肌营养不良的疾病进展

• 批准号: 7535922
• 负责人: RICHARD T MOXLEY
• 金额: $ 62.34万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7535922
• 关键词: 3' Untranslated Regions; Affect; Behavioral Genetics; Biochemical; Cell division; Cells; Clinical Trials; Cloning; Development; Disease Progression; End Point; Genetic Transcription; Genomics; Goals; Human; Impairment; Individual; Length; Life; Mediating; Methods; Monitor; Muscle; Muscle Cells; Mutation; Myopathy; Myotonic Dystrophy; Outcome; Pathogenesis; Pathway interactions; Positioning Attribute; Rate; Research; Somatic Cell; Therapeutic; Time; Transgenic Organisms; Up-Regulation; cohort; follow-up; functional disability; mouse model; mutant; postnatal; prospective; size

Disease Progression in Myotonic Dystrophy Research on myotonic dystrophy type 1 (DM1) has led to the recognition of a new paradigm for muscle disease. The mutation in DM1, an expanded CTG repeat in the 3' untranslated region of DMPK, is unstable in somatic cells. The expansion continues to increase in size in muscle cells during postnatal life, reaching lengths of several thousand repeats. The mechanisms underlying this unusual genetic behavior, and the relationships among increasing repeat length and onset or progression of DM1, have not been determined. Deleterious effects of the mutation are mediated by the mutant RNA, which contains an expanded CUG repeat (CUGexp). Recent findings in transgenic mouse models have identified several cellular pathways that are affected by CUGexp RNA, such as, MBNL1 sequestration and upregulation of CUGBP1 or NKX2.5. However, which of these mechanisms are primarily responsible for muscle degeneration in human DM1 is in question. This multifaceted project brings together a large collaborative team to study the mechanisms for repeat instability and the relationships among CTG repeat length, biochemical changes, and muscle impairment in individuals with DM1. Our goal is to focus therapeutic effort on the targets that are most pertinent to DM1 progression. Studies of pathogenesis will be tightly coordinated with prospective longitudinal follow up in a cohort of individuals with DM1. The goal of this analysis is to define rates of DM1 progression and determine which outcomes are most sensitive for monitoring disease progression and suitable as endpoints in clinical trials. Aim 1 employs a new method for cell free cloning of CTG repeats to study the effects of cell division, genomic position, transcription, and oxidative damage on stability of highly expanded CTG repeats in human cells. Aim 2 examines the relationships among repeat length, biochemical changes, and weakness in the same muscle. Aim 3 compares loss of muscle bulk and strength over time with functional impairments that are characterstic of DM1. Overall, this project will supply critical information that is needed to move forward with therapeutic development in DM1.

强直性肌营养不良的疾病进展 强直性肌营养不良1型（DM1）的研究导致了对肌肉的新范式的认识 疾病DM1中的突变是DMPK 3'非翻译区中的CTG重复扩增， 在体细胞中。在出生后的生活中，肌肉细胞的体积继续增加， 几千个重复的长度这种不寻常的遗传行为背后的机制， 增加的重复长度和DM 1的发作或进展之间的关系尚未确定。 突变的有害影响是由突变RNA介导的，其含有扩增的CUG 重复（CUGexp）。最近在转基因小鼠模型中的发现已经确定了几种细胞通路 受CUGexp RNA影响，如MBNL1螯合和CUGBP1或NKX2.5上调。 然而，这些机制中的哪一个是人类DM1肌肉退化的主要原因， 问题这个多方面的项目汇集了一个大型协作团队，研究 重复序列不稳定性以及CTG重复序列长度、生化变化和肌肉 DM1患者的症状。我们的目标是把治疗的重点放在那些 与DM1进展有关。发病机制的研究将与前瞻性研究密切配合。 对1型糖尿病患者队列进行纵向随访。本分析的目的是确定DM 1的发生率 并确定哪些结果对监测疾病进展最敏感， 适合作为临床试验的终点。目的1采用一种新的无细胞克隆CTG重复的方法， 研究细胞分裂、基因组位置、转录和氧化损伤对高度稳定性的影响， 在人类细胞中扩增CTG重复序列。目的2研究重复序列长度、生化指标和基因型之间的关系。 变化和同一块肌肉的弱点。目标3比较肌肉体积和力量随时间的损失 患有DM1型糖尿病的功能障碍。总体而言，该项目将提供关键信息， 这是推动DM 1治疗发展所必需的。