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; 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.

肌营养不良的疾病进展 关于1型肌发育症（DM1）的研究导致了人们对肌肉的新范式的认识 疾病。 DM1突变是DMPK的3'未翻译区域中扩展的CTG重复 在体细胞中。在产后生活期间，肌肉细胞的大小不断增加，达到 长度为几千重复。这种异常遗传行为的基础机制，以及 尚未确定重复长度和DM1的发作或进展的关系之间的关系。 突变的有害作用是由突变体RNA介导的，突变体RNA含有扩展的CUG 重复（cugexp）。转基因小鼠模型的最新发现已经鉴定了几种细胞途径 受CugeXP RNA的影响，例如，MBNL1隔离和CUGBP1或NKX2.5的上调。 但是，这些机制中的哪种主要负责人DM1的肌肉变性 问题。这个多方面的项目汇集了一个大型协作团队，以研究 重复不稳定性以及CTG重复长度，生化变化和肌肉之间的关系 DM1患者的损害。我们的目标是将治疗努力集中在最多的目标上 与DM1的进展相关。发病机理的研究将与前瞻性协调 DM1的个体中的纵向随访。该分析的目的是定义DM1的速率 进展并确定哪些结果对监测疾病进展和 适用于临床试验中的终点。 AIM 1采用一种新方法来无细胞CTG重复的克隆到 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 在人类细胞中扩展了CTG重复。 AIM 2检查重复长度，生化的关系 变化和相同肌肉的弱点。 AIM 3比较随着时间的推移的肌肉散装和力量的丧失 具有DM1特征的功能障碍。总体而言，该项目将提供关键信息 在DM1的治疗发展中，需要这是需要的。