MECHANISMS OF RNA-MEDIATED CNS PATHOGENESIS IN MYOTONIC DYSTOPHY

RNA介导的强直性肌营养不良中枢神经系统发病机制

基本信息

批准号：
8739678
负责人：
MAURICE SCOTT SWANSON
金额：
$ 35.6万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-15 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8739678
关键词：
Address Adult Affect Alternative Splicing Animal Model Autopsy Binding Brain Characteristics Complex Critiques Defect Development Disease Disease model Down-Regulation Embryo Evaluation Event Executive Dysfunction Family member Fetal Development Freezing Functional disorder Funding Future Genes Goals Grant Hereditary Disease Human Infiltration Knock-out Knockout Mice Learning Link Mediating Memory impairment Mental Retardation Microsatellite Repeats Minor Modeling Molecular Mus Muscular Dystrophies Myotonia Myotonic Dystrophy N-Methyl-D-Aspartate Receptors National Institute of Arthritis and Musculoskeletal and Skin Diseases Nervous System Physiology Neuraxis Neurodegenerative Disorders Neurons Pathogenesis Patients Perinatal Phenotype Poly A Powder dose form Protein Isoforms Proteins Protocols documentation Published Comment Publishing REM Sleep RNA RNA Splicing Research Sampling Seizures Skeletal Muscle Spliced Genes Synapses Systemic disease Testing Tissues Ultraviolet Rays Up-Regulation Work autistic behaviour base cerebral atrophy combinatorial crosslink disease characteristic disease mechanisms study disorder control drug development fetal gene synthesis model development mouse model nestin protein novel research study response therapeutic development therapy development tool

项目摘要

While myotonic dystrophy (DM) is classified as a muscular dystrophy, it is a progressive multi-systemic disease that has significant effects on central nervous system (CNS) function. These CNS manifestations include mental retardation and autistic behaviors in congenital DM and hypersomnia, executive dysfunction and cortical atrophy in the adult-onset form. Studies on the molecular basis of DM have revealed a novel disease mechanism, RNA-mediated pathogenesis, that involves the expansion of microsatellite C(C)TG repeats in two unrelated genes and the synthesis of toxic C(C)UG expansion RNAs. These pathogenic RNAs interfere with the normal alternative splicing functions of the CELF and MBNL proteins resulting in the persistence of, or reversion to, fetal isoforms in adult tissues. To determine if this RNA-mediated disease model is relevant to CNS dysfunction in DM, we have recently generated Mbnl2 knockout mice which recapitulate characteristic pathological features of the DM brain including abnormal REM sleep propensity and spatial memory deficits. In this proposal, we will first test the MBNL2 sequestration hypothesis for DM relevant CNS pathogenesis by demonstrating that transfer of MBNL2 from its normal RNA targets to C(C)UG repeats occurs in the DM brain. Next, we will determine if Mbnl2 knockout mice model the full range of DM CNS features and link specific mis-splicing events to characteristic disease manifestations. Finally, we will test the hypothesis that interactions between MBNL genes are disrupted in the congenital disease. These studies will provide novel animal models of adult-onset and congenital DM for future disease mechanism studies and the development of therapies that target the DM brain.

虽然强直性肌营养不良 (DM) 被归类为肌营养不良症，但它是一种进行性多系统疾病，对中枢神经系统 (CNS) 功能有显着影响。这些中枢神经系统表现包括先天性糖尿病中的智力低下和自闭症行为以及嗜睡症、成人发病形式中的执行功能障碍和皮质萎缩。对 DM 分子基础的研究揭示了一种新的疾病机制，即 RNA 介导的发病机制，涉及两个不相关基因中微卫星 C(C)TG 重复序列的扩展以及有毒 C(C)UG 扩展 RNA 的合成。这些致病性 RNA 干扰 CELF 和 MBNL 蛋白的正常选择性剪接功能，导致成人组织中胎儿亚型的持续存在或恢复。为了确定这种 RNA 介导的疾病模型是否与 DM 中的 CNS 功能障碍相关，我们最近培育了 Mbnl2 基因敲除小鼠，它们概括了 DM 大脑的特征性病理特征，包括异常的 REM 睡眠倾向和空间记忆缺陷。在本提案中，我们将首先通过证明 MBNL2 从其正常 RNA 靶标转移到 DM 大脑中发生的 C(C)UG 重复序列，来测试 DM 相关 CNS 发病机制的 MBNL2 隔离假说。接下来，我们将确定 Mbnl2 敲除小鼠是否能够模拟全部 DM CNS 特征，并将特定的错误剪接事件与特征性疾病表现联系起来。最后，我们将检验先天性疾病中 MBNL 基因之间的相互作用被破坏的假设。这些研究将为未来的疾病机制研究和针对糖尿病大脑的疗法的开发提供成人发病和先天性糖尿病的新动物模型。