Coupling of muscle blind-dependent RNA processing to the circadian clock in neuronal homeostasis and sleep

肌肉盲依赖性RNA加工与神经元稳态和睡眠中生物钟的耦合

• 批准号: 9913989
• 负责人: Mark Perelis
• 金额: $ 6.74万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913989
• 关键词: Adult; Affect; Animals; Biology; Brain; CRISPR/Cas technology; CUG repeat; Cardiac; Cardiomyopathies; Circadian Dysregulation; Circadian Rhythms; Coupling; DNA; Data; Development; Dimensions; Disease; Disease model; Event; Excessive Daytime Sleepiness; Family; Future; Gene Expression; Genes; Genetic; Genome; Health; Homeostasis; Human; Link; Maintenance; Mediating; Modeling; Molecular; Mus; Muscle; Muscular Atrophy; Muscular Dystrophies; Mutation; Myotonia; Myotonic Dystrophy; Myotonic dystrophy type 1; Neurodegenerative Disorders; Neuromuscular Diseases; Neurons; Pathway interactions; Patients; Periodicity; Peripheral; Phenotype; Physical Performance; Population; Property; Protein Inhibition; Proteins; RNA; RNA Processing; RNA Splicing; RNA-Binding Proteins; RNA-Protein Interaction; Reagent; Research; Role; Signal Pathway; Skeletal Muscle; Sleep; Sleep Disorders; Sleep disturbances; Symptoms; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Trinucleotide Repeat Expansion; Variant; base; blind; circadian; circadian behavioral rhythms; circadian pacemaker; cognitive performance; comorbidity; disease phenotype; genome-wide; induced pluripotent stem cell; insight; molecular clock; neuron loss; protein expression; screening; stem cells; tool; virtual

Abstract: Excessive daytime sleepiness and other sleep perturbances are frequent and serious comorbidities in patients with myotonic dystrophy type 1 (DM1), a multi-system disease otherwise characterized by myotonia and cardiomyopathy. It is well-established that skeletal-muscle and cardiac phenotypes of DM1 are caused by dysregulation of muscle-specific splicing events due to sequestration of MBNL family RNA binding proteins (RBPs) by transcribed repeat RNAs; however, the molecular mechanisms underlying sleep disorders in DM1 are poorly understood. Loss of neuronal MBNL2 in mice recapitulates the CNS features of DM1 with no muscle or cardiac involvement and Mbnl2-/- mice display mis-timed sleep episodes and a loss of diurnal rhythmicity in RNA processing events, suggesting that disruption of circadian rhythm is central to DM1 pathobiology. I therefore propose that inhibition of MBNL proteins perturbs the core circadian timing mechanism leading to mis-allocation of sleep in DM1 and potentially contributing to central and peripheral disease phenotypes. To gain insight into interactions between MBNL and the circadian clock I have developed animal- and human iPSC-based models to define RNA processing events that alter molecular and behavioral circadian rhythms in DM1. My proposed studies will precisely determine the impact of MBNL inhibition by repeat RNA on the entrainment and maintenance of circadian rhythms within sleep-regulatory neurons and pinpoint specific MBNL-mediated RNA processing targets that disrupt the molecular clock and impair sleep in DM1. If successful these studies will define molecular pathways underlying sleep disorder in the context DM1-linked mutations and provide a springboard for the future development of disease models for therapeutic discovery in sleep biology.

摘要： 日间过度嗜睡和其他睡眠紊乱是患者常见且严重的合并症 强直性肌营养不良1型（DM 1），一种多系统疾病，以肌强直为特征， 心肌病已经确定DM 1的肌肉和心脏表型是由以下因素引起的： 由于MBNL家族RNA结合蛋白的螯合导致的肌肉特异性剪接事件的失调 （RBP）的转录重复RNA;然而，DM 1睡眠障碍的分子机制 我们对此知之甚少。小鼠中神经元MBNL 2的缺失重现了无肌肉的DM 1的CNS特征 或心脏受累，Mbnl 2-/-小鼠显示出错误的睡眠时间和昼夜节律的丧失， RNA加工事件，表明昼夜节律的破坏是DM 1病理生物学的核心。我 因此，提出MBNL蛋白的抑制扰乱了核心昼夜节律计时机制，导致 DM 1中睡眠分配错误，可能导致中枢和外周疾病表型。到 深入了解MBNL和生物钟之间的相互作用，我已经开发了动物和人类 基于iPSC的模型，用于定义改变生物体内分子和行为昼夜节律的RNA加工事件， DM1。我提出的研究将精确地确定重复RNA对MBNL抑制的影响。 在睡眠调节神经元内的昼夜节律的诱导和维持， MBNL介导的RNA加工靶点破坏DM 1中的分子钟并损害睡眠。如果 成功的这些研究将确定在DM 1相关的背景下睡眠障碍的分子途径。 突变，并为未来开发用于治疗发现的疾病模型提供跳板， 睡眠生物学