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: 9569715
• 负责人: LOUIS J. PTACEK
• 金额: $ 57.88万
• 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/9569715
• 关键词: Advanced Sleep Phase Syndrome; Affect; Age; Aging; Algorithms; Animal Model; Area; Asthma; Attention; Behavior; Behavioral; Behavioral Genetics; Biology; Blood specimen; Candidate Disease Gene; Cardiovascular Diseases; Childhood; Circadian Rhythms; Clinical; Clinical Data; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Collection; Complex; 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; Regulation; 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; circadian pacemaker; 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 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.

摘要 在地球上，生物体已经进化出同步代谢和生理功能的机制 24小时光照/黑暗循环。有趣的是，许多人类疾病都与昼夜节律有关， 天当穿越时区旅行时，我们的睡眠模式，精神警觉性，饮食习惯和许多 其他生理过程暂时遭受“异相”的后果，直到我们适应 新的时区。此外，很大一部分人口在“墓地”轮班，包括 卫生保健工作者、警察、卡车司机和工厂工人。最近的研究表明， 生物钟与许多疾病，包括：哮喘，癌症，代谢综合征，心血管 疾病、精神疾病和学习障碍。大量的知识来自于研究 模式生物昼夜节律的遗传和分子基础。尽管昼夜节律的重要性 生物钟对我们生理和行为的各个方面都有重要影响，因此，我们有机会探讨人类的生物钟， 随着人们对孟德尔昼夜节律变体的认识（家族性晚期睡眠阶段， FASP）。我们鉴定了FASP，收集了许多家族，并定位和克隆了第一个FASP基因。我们 接着，他鉴定了总共6个FASP基因，并建立了所有这些基因的动物模型。尽管如此， 大多数FASP家族在已知的时钟基因中没有突变。在这份提案中，我们提出了一个计划， 继续收集更多的家族（目标1），在>50岁的先证者中进行全外显子组测序， “无法解释的”FASP家族，并在变体中筛选以确定新的昼夜节律/FASP 基因/突变（Aim 2）。最后，由于前1-2年将集中于鉴定新的FASP基因，我们 拟对TIMELESS基因中的人FASP突变进行体外和体内研究（目的3）。 在人类和小鼠模型中的平行研究将协同解剖人类对FASP的理解 探索我们的生物钟与其他生物的生物钟之间的相似性和差异。 研究人类昼夜节律的分子机制将对我们的研究产生巨大的影响。 了解人类健康和疾病。它还应该导致药理学的新策略， 操纵人体生物钟，以改善时差，各种与生物钟有关的睡眠和精神病的治疗 疾病，以及其他人类疾病。对人类生物钟基因和突变的了解将 使开发更好的治疗ASPS的老化，时差和其他睡眠障碍。