Probing genetics and biology of human circadian function

探索人类昼夜节律功能的遗传学和生物学

• 批准号: 10231072
• 负责人: LOUIS J. PTACEK
• 金额: $ 57.62万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231072
• 关键词: Advanced Sleep Phase Syndrome; Affect; Age; Aging; Algorithms; Animal Model; Area; Asthma; Attention; Bacterial Artificial Chromosomes; Behavior; Behavioral Genetics; Biology; Blood specimen; Candidate Disease Gene; Cardiovascular Diseases; Childhood; Circadian Dysregulation; Circadian Rhythms; Clinical; Clinical Data; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Collection; DNA; Development; Diagnosis; Diet Habits; Disease; Family; Gene Mutation; Genes; Genetic; Genetic study; Health; Health Personnel; Hour; Human; Human Biology; Impairment; In Vitro; Individual; Investigation; Jet Lag Syndrome; Knowledge; Lead; Learning Disorders; Life; Light; Link; Malignant Neoplasms; Maps; Mental disorders; Metabolic; Metabolic syndrome; Molecular; Mutation; Nature; Nuclear; Organism; Pathway interactions; Pattern; Periodicity; Pharmacology; Phase; Phenotype; Physiological; Physiological Processes; Physiology; Planet Earth; Police officer; Population; Proteins; Psyche structure; Public Domains; RNA Splicing; Regulatory Pathway; Repressor Proteins; Resources; Role; Sampling; Schedule; Series; Sleep; Sleep Disorders; Sleep Wake Cycle; Technology; Time; Transgenic Organisms; Travel; Variant; Work; alertness; autosomal dominant trait; base; behavioral phenotyping; causal variant; circadian; circadian pacemaker; circadian regulation; clinical phenotype; exome sequencing; family genetics; genetic linkage; genetic pedigree; genetic variant; human disease; human model; improved; in vivo; insight; mouse model; next generation sequencing; novel; proband; sleep behavior; sleep quality; success; young adult

ABSTRACT On planet earth, organisms have evolved mechanisms to synchronize metabolic and physiological functions with the ~24 hour light/dark cycle. Interestingly, many human diseases have associations with the circadian day. When traveling across time zones, our sleep-wake patterns, mental alertness, eating habits and many other physiological processes temporarily suffer the consequences of being “out of phase” until we adjust to the new time zone. In addition, a significant portion of the population works the ‘graveyard’ shift, including health care workers, police officers, truck drivers and factory workers. Recent studies have linked disruption of the circadian clock with numerous ailments, including: asthma, cancer, metabolic syndrome, cardiovascular diseases, psychiatric diseases, and learning disorders. Tremendous knowledge has come from studying the genetic and molecular basis of circadian rhythms in model organisms. Despite the importance of the circadian clock to all aspects of our physiology and behavior, the opportunity to probe the human circadian clock only became possible with the recognition of Mendelian circadian variants in people (familial advanced sleep-phase, FASP). We characterized FASP, collected many families, and mapped and cloned the first FASP genes. We went on to identify a total of 6 FASP genes and have generated animal models of all of them. Still, a large majority of FASP families do not have mutations in the known clock genes. In this proposal, we outline a plan to continue collecting additional families (Aim 1), to perform whole exome sequencing in probands from >50 ‘unexplained’ FASP families, and to sift among the variants to identify novel circadian rhythm/FASP genes/mutations (Aim 2). Finally, since the first 1-2 years will be focused on identifying novel FASP genes, we propose to perform in vitro and in vivo studies of a human FASP mutation in the TIMELESS gene (Aim 3). Parallel studies in humans and mouse models will synergize in dissecting understanding of FASP in humans and exploring the similarities and differences between our circadian clocks vs. those of other organisms. Studying the molecular mechanism of human circadian rhythmicity will have an enormous impact on our understanding of human health & disease. It should also lead to new strategies for pharmacological manipulation of the human clock to improve the treatment of jet-lag, various clock-related sleep and psychiatric disorders, as well as other human diseases. Understanding of the human clock genes and mutations will enable development of better therapies for ASPS of aging, jet lag, and other sleep disorders.

抽象的 在地球上，生物具有发展的机制来同步代谢和物理功能 与〜24小时的光线/黑暗周期。有趣的是，许多人类疾病与昼夜节律有关联 天。在跨时区旅行时，我们的睡眠效果模式，精神警觉，饮食习惯和许多 其他物理过程暂时遭受“阶段”的后果，直到我们适应 新时区。此外，很大一部分人口在“墓地”转变，包括 卫生保健工作者，警察，卡车司机和工厂工人。最近的研究与中断有关 昼夜节律有很多疾病，包括：哮喘，癌症，代谢综合征，心血管 疾病，精神病和学习障碍。巨大的知识来自研究 模型生物中昼夜节律的遗传和分子基础。尽管昼夜节律很重要 时钟到我们生理和行为的各个方面 通过认识到人类的孟德尔昼夜节律变体（家族性先进的睡眠期， FASP）。我们表征了FASP，收集了许多家庭，并映射并克隆了第一个FASP基因。我们 继续确定了总共6个FASP基因，并产生了所有动物模型。仍然，一个大 大多数FASP家族在已知的时钟基因中没有突变。在此提案中，我们概述了一个计划 继续收集其他家庭（AIM 1），以> 50的概率进行整个外显子组测序 “无法解释的” FASP家族，并在变体中筛选以识别新颖的昼夜节律/fasp 基因/突变（AIM 2）。最后，由于最初的1 - 2年将集中在识别新型FASP基因上，因此我们 对永恒基因中人体FASP突变进行体外和体内研究的建议（AIM 3）。 在人类和小鼠模型中的平行研究将协同剖析对人类FASP的理解 并探索昼夜节律与其他生物的相似之处和差异。 研究人类昼夜节律的分子机制将对我们的我们产生巨大影响 了解人类健康与疾病。它还应该导致制药的新策略 操纵人类时钟以改善喷气滞后，各种与时钟相关的睡眠和精神病的处理 疾病以及其他人类疾病。了解人类时钟基因和突变的理解 为衰老，喷气滞后和其他睡眠障碍提供更好的疗法。