Circadian and Sleep Programming in Angelman Syndrome Mouse Models

天使综合症小鼠模型的昼夜节律和睡眠编程

• 批准号: 9427801
• 负责人: CARL Hirschie JOHNSON
• 金额: $ 35.32万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9427801
• 关键词: ARNTL gene; Affect; Age; Alleles; Angelman Syndrome; Antisense Oligonucleotides; Architecture; Area; Autistic Disorder; Behavior; Behavioral; Biological Assay; Biological Clocks; Biological Markers; Biological Models; Brain; Cardiovascular Diseases; Circadian Rhythms; Clock protein; Cognitive; Coupled; Darkness; Defect; Development; Developmental Delay Disorders; Disease; Embryo; Family; Feedback; Feeding behaviors; Fibroblasts; Foundations; Gene Dosage; Gene Expression; Genes; Genetic; Genetic Transcription; Health; Human; Impairment; In Vitro; Investigation; Jet Lag Syndrome; Kinetics; Ligase; Light; Lighting; Link; Malignant Neoplasms; Mammals; Mediating; Mental Depression; Mental Health; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Molecular; Molecular Models; Molecular Target; Motor Activity; Mus; Neurodevelopmental Disorder; Neurons; Obesity; Periodicity; Pharmacological Treatment; Pharmacology; Phase; Phenotype; Process; Property; Public Health; Regulation; Research; Role; Seizures; Sleep; Sleep Disorders; Sleep disturbances; Speech; Syndrome; System; Testing; Third ventricle structure; Tissues; Topotecan; Treatment Efficacy; UBE3A gene; Ubiquitination; base; circadian pacemaker; clinically relevant; cognitive development; dosage; experimental study; fascinate; gene environment interaction; gene product; human subject; imprint; in vivo; molecular modeling; mouse model; neurodevelopment; novel; overexpression; physical conditioning; protein degradation; shift work; suprachiasmatic nucleus; ubiquitin ligase

Project Summary/Abstract: Circadian (daily) rhythms regulate myriad behavioral and molecular processes including locomotor activity, sleep timing, feeding behavior, metabolism, and gene expression. These biological "clocks" are a crucial component of human health, and improper functioning of this system is associated with sleep/wake disorders, metabolic syndrome, and obesity. The current molecular model for the circadian clock mechanism comprises autoregulatory transcriptional & translational feedback loops of central clock genes that necessitate rhythmic synthesis and degradation of clock gene products. We have found that the effective gene dosage of the Ube3a gene that encodes an ubiquitin ligase (involved in protein degradation) regulates fundamental properties of the circadian clock system in mammals. The expression level of the Ube3a gene is crucial for normal neurodevelopment. For example, reduced dosage of Ube3a leads to Angelman Syndrome (AS) and increased dosage/activity can result in autism. Therefore, the level of expression of Ube3a is critical for normal cognitive development, and the thesis of this project is that balanced expression of Ube3a is key for stable circadian rhythmicity as well. AS is a disorder characterized by cognitive/developmental delays, speech impairment, sleep disorders, and seizures. The paternal allele of Ube3a is imprinted (silenced) in neurons, and most cases of AS result from a deletion of the maternal Ube3a allele that further downregulates Ube3a in neurons. Mouse models have been generated that have (i) a deletion of the maternal Ube3a allele (model of AS), and (ii) extra copies of Ube3a (model of autism); these models enable tests of our hypothesis, which is that Ube3a expression affects the plasticity of circadian rhythms and that environmental, genetic, and/or pharmacological treatments can be identified that compensate for the loss of Ube3a expression. This hypothesis will be tested by manipulating environmental, genetic, and developmental conditions to affect the circadian system in mouse models of AS. Specific pharmacological treatments will be tested for their potential in reversing the circadian phenotypes of AS models to use as a basis for identifying a biomarker to be used with human subjects. Clock proteins will be identified as molecular targets of Ube3a-mediated ubiquitination. Finally, an Ube3a overexpressing mouse model will be tested to determine if Ube3a overexpression has reciprocal effects to the Ube3a null of AS models. This project represents a novel area of investigation that has the potential to enhance health-related research; its overall significance is (i) to elucidate the role of ubiquitination and imprinting in the circadian mechanism, and (ii) to identify treatments that ameliorate the circadian disorders of Ube3a imprinting in mouse models. The answers to these questions will help us to understand fundamental circadian organization and plasticity in this fascinating–and potentially clinically relevant–example of gene X environment interaction.

项目摘要/摘要： 昼夜节律（每日）调节无数的行为和分子过程，包括运动活动、 睡眠时间、进食行为、新陈代谢和基因表达是至关重要的。 人类健康的组成部分，该系统的不当功能与睡眠/觉醒障碍有关， 目前生物钟机制的分子模型包括代谢综合征和肥胖。 中央时钟基因的自动调节转录和翻译反馈环路，需要有节奏的 我们发现了Ube3a的有效基因剂量。 编码泛素连接酶（参与蛋白质降解）的基因调节泛素连接酶的基本特性 哺乳动物的生物钟系统。 例如，Ube3a 基因的表达水平降低对于正常神经发育至关重要。 Ube3a 的剂量会导致天使综合症 (AS)，而剂量/活动增加会导致自闭症。 因此，Ube3a的表达水平对于正常认知发展至关重要，本论文的论文 该项目认为，Ube3a 的平衡表达是稳定昼夜节律的关键，AS 也是一种疾病。 其特征是认知/发育迟缓、言语障碍、睡眠障碍和癫痫发作。 Ube3a 的父系等位基因在神经元中被印记（沉默），大多数 AS 病例是由该基因缺失引起的 已生成进一步下调神经元中 Ube3a 的母体 Ube3a 等位基因。 (i) 母体 Ube3a 等位基因缺失（AS 模型），以及 (ii) Ube3a 额外拷贝（自闭症模型）； 这些模型能够检验我们的假设，即 Ube3a 表达影响昼夜节律的可塑性 节律，并且可以确定环境、遗传和/或药物治疗来补偿 该假设将通过操纵环境、遗传和基因来检验。 影响 AS 小鼠模型昼夜节律系统的发育条件。 将测试治疗方法在逆转 AS 模型昼夜节律表型方面的潜力，以用作 识别用于人类受试者的生物标志物的基础将被识别为分子。 最后，将测试 Ube3a 过度表达的小鼠模型。 确定 Ube3a 过度表达是否与 AS 模型的 Ube3a 无效具有交互作用。 该项目代表了一个新的研究领域，有潜力加强与健康相关的研究 研究；其总体意义是（i）阐明泛素化和印记在昼夜节律中的作用 机制，以及 (ii) 确定改善小鼠 Ube3a 印记昼夜节律紊乱的治疗方法 这些问题的答案将帮助我们了解基本的昼夜节律组织和 这个引人入胜且可能具有临床相关性的 X 基因环境相互作用示例中的可塑性。