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: 10005495
• 负责人: CARL Hirschie JOHNSON
• 金额: $ 26.89万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005495
• 关键词: ARNTL gene; Affect; Age; Alleles; Angelman Syndrome; Antisense Oligonucleotides; Architecture; Area; Behavior; Behavioral; Biological Assay; Biological Clocks; Biological Markers; Biological Models; Brain; Cardiovascular Diseases; Circadian Rhythms; Clock protein; Cognitive; Coupled; Defect; Development; Developmental Delay Disorders; Disease; Embryo; Family; Feedback; Feeding behaviors; Fibroblasts; Foundations; Gene Dosage; Gene Expression; Genes; Genetic; Genetic Transcription; Health; Human; In Vitro; Investigation; Jet Lag Syndrome; Kinetics; Ligase; Lighting; Link; Malignant Neoplasms; Mammals; Mediating; Mental Depression; Mental Health; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Molecular; Molecular Target; Motor Activity; Mus; Neurodevelopmental Disorder; Neurons; Obesity; Periodicity; Personal Satisfaction; Pharmacological Treatment; Pharmacology; Phase; Phenotype; Process; Property; Public Health; Research; Role; Seizures; Sleep; Sleep Disorders; Sleep disturbances; Speech; Syndrome; System; Testing; Third ventricle structure; Tissues; Topotecan; Treatment Efficacy; UBE3A gene; Ubiquitination; autism spectrum disorder; base; circadian; circadian pacemaker; circadian regulation; clinically relevant; cognitive development; dosage; experimental study; fascinate; gene environment interaction; gene product; human subject; imprint; in vivo; in vivo evaluation; 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.

项目总结/文摘:

项目成果

Circadian Rhythms and Sleep Are Dependent Upon Expression Levels of Key Ubiquitin Ligase Ube3a.

• DOI: 10.3389/fnbeh.2022.837523
• 发表时间: 2022
• 期刊: Frontiers in behavioral neuroscience
• 影响因子: 3
• 作者: Shi SQ;Mahoney CE;Houdek P;Zhao W;Anderson MP;Zhuo X;Beaudet A;Sumova A;Scammell TE;Johnson CH
• 通讯作者: Johnson CH

Targeted modification of the Per2 clock gene alters circadian function in mPer2luciferase (mPer2Luc) mice.

• DOI: 10.1371/journal.pcbi.1008987
• 发表时间: 2021-05
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Ralph MR;Shi SQ;Johnson CH;Houdek P;Shrestha TC;Crosby P;O'Neill JS;Sládek M;Stinchcombe AR;Sumová A
• 通讯作者: Sumová A