Genetic and molecular basis of circadian rhythm disorders

昼夜节律在24小时内调节人类的行为和生理，以优化过程，从 基因表达对认知的影响。这些节律的失调与睡眠障碍、认知障碍有关 体能、癌症、慢性代谢性疾病和神经系统疾病。尽管重要的是 昼夜节律对人类健康的影响及其在模式生物中的基本作用，人们知之甚少 关于人类昼夜节律与我们的健康和生理之间的生物学联系。我们建议 通过对极端昼夜节律紊乱的测序来识别与昼夜节律有关的新的遗传因素 来自临床队列的患者(n~200)。晚期睡眠相综合征(ASPS)与睡眠延迟 综合征(DSPs)是一种遗传性的昼夜节律的神经睡眠障碍，表现为极端 改变了睡眠时间。家族性研究发现编码人类免疫缺陷病毒分子成分的基因突变 生物钟(PER2，PER3)或调节时钟的速度/速度(CSNK1D)，导致极快的前进 或睡眠开始延迟。我们假设ASPS和DSS受试者存在罕见的功能丧失突变 在生物钟的组成部分中，包括输入/输出通路和核心分子钟。这 假设将在两个具体目标中进行检验：目标1将确定与 临床队列中的晚期和睡眠延迟综合征。我会学习昼夜节律的表型 疾病和外显子组测序和分析。目标2将确定这种疾病的潜在机制 通过确定ASPS和DSPs基因突变对细胞昼夜节律和 筛选新的治疗化合物。通过目标2，我将发展昼夜细胞培养分析的技能。 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DSS的新的致病遗传因素。通过这些结果，我们将阐明新的基因 以及昼夜节律的潜在途径。这些发现将为治疗学开辟潜在的新途径 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的慢性病开辟了新的途径。至 实现我的长期职业目标，成为时间生物学领域的领先人类遗传学家之一，我 我将把我目前在全基因组研究复杂性状的共同变异方面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 进球。本K01中提出的研究将作为获得此培训的必要垫脚石。

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.