Myotonic Dystrophy: Molecular Pathophysiology and CNS Effects

强直性肌营养不良：分子病理生理学和中枢神经系统影响

• 批准号: 8257590
• 负责人: Laura P.W Ranum
• 金额: $ 46.56万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8257590
• 关键词: Myotonic; Dystrophy; Molecular; Pathophysiology; CNS

Myotonic dystrophy type 1 (DM1) is caused by a CTG expansion mutation located in the 3' untranslated portion of the dystrophica myotonica protein kinase gene. The identification and characterization of RNAbinding proteins that interact with expanded CUG repeats and the discovery that a similar transcribed but untranslated CCTG expansion in an intron causes myotonic dystrophy type 2 (DM2), have uncovered a new type of mechanism in which microsatellite expansion mutations cause disease through an RNA gain of function mechanism in which CUG and CCUG expansion transcripts lead to the dysregulation of key RNAbinding proteins, including muscleblind (MbnH) and CUG-binding protein (CUG-BP), which in turn lead to the downstream dysregulation of specific set of genes that cause the multisystemic features common to both diseases. Although the CNS deficits are one of the most clinically significant aspects of DM, the molecular mechanisms underlying these changes are unclear. Only DM1 causes developmental defects, including mental retardation, but both forms of DM result in degenerative CNS effects that have not yet been well characterized. The focus of this proposal is to characterize the CNS effects of the DM1 and DM2 mutations in patients through imaging studies and neuropsychological testing and to relate these changes to the underlying molecular deficits through the generation and characterization of mouse models. To accomplish these goals the following Projects and Cores are proposed as part of our overall Program entitled: Myotonic Dystrophy: Molecular Pathophysiology and CNS Effects. Project 1: Temporal/spatial RNA expression effects in DM1 and DM2 Project 2: Mechanisms of RNA-Mediated CNS Pathogenesis in Myotonic Dystrophy Project 3: Structural and Functional CNS Changes in Children with Myotonic Dystrophy Type 1 Core A: Neuropathology and Optical Imaging Core Core B: Administrative Core

强直性肌营养不良 1 型 (DM1) 是由位于 3' 非翻译区的 CTG 扩展突变引起的 肌强直营养不良蛋白激酶基因的一部分。 RNA结合的鉴定和表征 与扩展的 CUG 重复相互作用的蛋白质，并发现类似的转录但 内含子中未翻译的 CCTG 扩增导致强直性肌营养不良 2 型 (DM2)，发现了一种新的 微卫星扩增突变通过 RNA 增加导致疾病的机制类型 CUG和CCUG扩增转录物导致关键RNA结合失调的功能机制 蛋白质，包括肌肉盲 (MbnH) 和 CUG 结合蛋白 (CUG-BP)，这反过来又导致 特定基因组的下游失调，导致两者共同的多系统特征 疾病。尽管中枢神经系统缺陷是 DM 临床上最重要的方面之一，但分子生物学 这些变化背后的机制尚不清楚。只有 DM1 会导致发育缺陷，包括 智力低下，但这两种形式的 DM 都会导致中枢神经系统退行性影响，但尚未得到很好的解决 特点。该提案的重点是表征 DM1 和 DM2 突变对 CNS 的影响 通过影像学研究和神经心理学测试对患者进行观察，并将这些变化与 通过小鼠模型的生成和表征来揭示潜在的分子缺陷。为了完成 为了实现这些目标，我们提出了以下项目和核心，作为我们题为“肌强直”的总体计划的一部分 营养不良：分子病理生理学和中枢神经系统影响。 项目1：DM1和DM2中的时间/空间RNA表达效应 项目2：RNA介导的强直性肌营养不良中枢神经系统发病机制 项目 3：1 型强直性肌营养不良儿童的中枢神经系统结构和功能变化 核心 A：神经病理学和光学成像核心 核心 B：行政核心