Genetic and molecular basis of circadian rhythm disorders

昼夜节律紊乱的遗传和分子基础

• 批准号: 10369051
• 负责人: Jacqueline Marie Lane
• 金额: --
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-05 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369051
• 关键词: ARNTL gene; Advanced Sleep Phase Syndrome; Advisory Committees; Affect; Animal Model; Australia; Behavior; Biological; Biological Assay; Biological Clocks; Biology; Cardiometabolic Disease; Cell Culture Techniques; Cells; Chemicals; Chronic; Chronic Disease; Chronobiology; Circadian Dysregulation; Circadian Rhythm Disorder; Circadian Rhythms; Clinic; Clinical; Cognition; Complex; Computerized Medical Record; Coupled; DNA Sequence Alteration; Data; Delayed Sleep Phase Syndrome; Development; Disease; Dyslipidemias; Environment; Family; Functional disorder; Gene Expression; General Hospitals; Genes; Genetic; Genetic study; Goals; Health; Healthcare; Hour; Human; Individual; Inherited; Institutes; Intervention; Investigation; Israel; Jet Lag Syndrome; Learning; Length; Libraries; Light; Link; Luciferases; Malignant Neoplasms; Massachusetts; Measures; Medicine; Mental disorders; Metabolic Diseases; Methods; Molecular; Mutation; Neurologic; Non-Insulin-Dependent Diabetes Mellitus; Output; Pathway interactions; Patients; Periodicity; Personal Satisfaction; Pharmacology; Phase; Phenotype; Physical Performance; Physiology; Positioning Attribute; Principal Investigator; Process; Rare Diseases; Reporter; Research; Research Personnel; Research Training; Role; Sampling; Sleep; Sleep Disorders; Speed; System; Techniques; Testing; Therapeutic; Training; Variant; base; biobank; cardiometabolic risk; career; causal variant; cell type; circadian; circadian biology; circadian pacemaker; circadian regulation; cognitive performance; cohort; design; exome; exome sequencing; genetic profiling; genetic variant; genome-wide analysis; loss of function; loss of function mutation; molecular clock; multi-ethnic; mutant; nervous system disorder; novel; novel therapeutics; precision medicine; process optimization; promoter; rare variant; screening; skills; sleep onset; small molecule; training project; trait

Circadian rhythms regulate human behavior and physiology within the 24 hour day to optimize processes, from gene expression to cognition. Dysregulation of those rhythms are associated with sleep disorders, cognitive and physical performance, cancer, and chronic metabolic and neurologic disease. Despite the importance of circadian rhythms to human health and their fundamental role demonstrated in model organisms, little is known about the biological connection between human circadian rhythms and our health and physiology. We propose to identify novel genetic factors involved in circadian rhythms by sequencing extreme circadian rhythm disorder patients from clinical cohorts (n~200). Advanced Sleep Phase Syndrome (ASPS) and Delayed Sleep Phase Syndrome (DSPS) are inherited neurological sleep disorders of the circadian clock, which present as extremely shifted sleep timing. Familial studies identified mutations in genes encoding molecular components of the circadian clock (PER2, PER3) or regulating the speed/pace of the clock (CSNK1D), causing extreme advance or delay in sleep onset. We hypothesize that ASPS and DSPS subjects harbor rare loss-of-function mutations in components of the circadian clock, including input/output pathways and the core molecular clock. This hypothesis will be tested in 2 specific aims: Aim 1 will identify genetic variants robustly associated with Advanced and Delayed Sleep Phase Syndrome in clinical cohorts. I will learn phenotyping of circadian disorders and exome sequencing and analysis. Aim 2 will determine the mechanisms underlying the disease process by determining the function of ASPS and DSPS genetic mutations on cellular circadian rhythms and screening for novel therapeutic compounds. Through Aim 2 I will develop skills in circadian cell culture assays and associated analysis techniques, as well as learn compound screening. The results of this study will identify new causal genetic factors for ASPS and DSPS. Through these results we will elucidate novel genes and pathways underlying circadian regulation. These findings will open potential new avenues of therapeutics for rare circadian rhythms disorders, increase our understanding of the basic mechanisms of circadian biology, and open new avenues for treatment of more common circadian rhythm associated chronic diseases. To achieve my long-term career goal to be one of the leading human geneticists in the field of chronobiology, I will expand my current expertise in genome-wide studies of common variation in complex traits into circadian clinical sample phenotyping and exome sequencing identification of causal rare variants to achieve my career goal. The research proposed in this K01 will serve as an essential stepping stone to acquire this training.

昼夜节律调节人类的行为和生理在24小时内的一天，以优化过程，从 基因表达到认知。这些节律的失调与睡眠障碍、认知功能障碍、 和身体表现，癌症，慢性代谢和神经系统疾病。尽管重要的是 昼夜节律对人类健康及其在模式生物中的基本作用，知之甚少 关于人类生理节奏和我们的健康和生理之间的生物学联系。我们提出 通过对极端昼夜节律紊乱进行测序， 来自临床队列的患者（n~200）。睡眠时相提前综合征（ASPS）和睡眠时相延迟 综合征（DSPS）是遗传性神经睡眠障碍的昼夜节律钟，这是目前极端 改变睡眠时间家族性研究确定了编码基因突变的分子组成部分， 昼夜节律钟（PER 2，PER 3）或调节时钟的速度/步伐（CSNK 1D），导致极端提前 或延迟入睡。我们假设ASPS和DSPS受试者携带罕见的功能缺失突变 生物钟的组成部分，包括输入/输出途径和核心分子钟。这 假设将在2个具体目标中进行测试：目标1将识别与以下疾病强烈相关的遗传变异： 临床队列中的晚期和延迟睡眠期综合征。我将学习生物钟的表型 疾病和外显子组测序和分析。目标2将确定疾病的潜在机制 通过确定ASPS和DSPS基因突变对细胞昼夜节律的功能， 筛选新的治疗化合物。通过目标2，我将发展昼夜细胞培养试验的技能 和相关的分析技术，以及学习化合物筛选。这项研究的结果将 确定ASPS和DSPS新的致病遗传因素。通过这些结果，我们将阐明新的基因 和生理节律调节的基础途径。这些发现将开辟潜在的新的治疗途径 对于罕见的昼夜节律紊乱，增加我们对昼夜节律生物学基本机制的理解， 并为治疗更常见的昼夜节律相关慢性疾病开辟了新的途径。到 实现我的长期职业目标是成为时间生物学领域领先的人类遗传学家之一，我 我将把我目前在全基因组研究复杂性状中常见变异的专业知识扩展到昼夜节律 临床样本表型和外显子组测序鉴定致病罕见变异，以实现我的职业生涯 目标.本K 01中提出的研究将作为获得此培训的重要垫脚石。