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.

抽象的 在地球上，生物体已经进化出同步代谢和生理功能的机制 大约 24 小时的光/暗周期。有趣的是，许多人类疾病都与昼夜节律有关 天。跨越时区旅行时，我们的睡眠-觉醒模式、精神警觉性、饮食习惯等 其他生理过程暂时遭受“不同步”的后果，直到我们适应 新时区。此外，很大一部分人在“墓地”轮班，包括 医护人员、警察、卡车司机和工厂工人。最近的研究表明，破坏 生物钟与许多疾病有关，包括：哮喘、癌症、代谢综合征、心血管疾病 疾病、精神疾病和学习障碍。大量的知识来自于研究 模型生物昼夜节律的遗传和分子基础。尽管昼夜节律很重要 我们生理和行为各个方面的时钟，只有探索人类生物钟的机会 随着人们对孟德尔昼夜节律变异的认识（家族性提前睡眠阶段、 快速安全服务计划）。我们对 FASP 进行了表征，收集了许多家族，并绘制并克隆了第一个 FASP 基因。我们 随后总共鉴定了 6 个 FASP 基因，并生成了所有这些基因的动物模型。尽管如此，一个大 大多数 FASP 家族的已知时钟基因没有突变。在本提案中，我们概述了一项计划 继续收集更多家庭（目标 1），对超过 50 个先证者进行全外显子测序 “无法解释的”FASP 家族，并筛选变体以识别新的昼夜节律/FASP 基因/突变（目标 2）。最后，由于前 1-2 年的重点是识别新的 FASP 基因，我们 提议对 TIMELESS 基因中的人类 FASP 突变进行体外和体内研究（目标 3）。 人类和小鼠模型的平行研究将在深入了解人类 FASP 方面发挥协同作用 并探索我们的生物钟与其他生物体的生物钟之间的异同。 研究人体昼夜节律的分子机制将对我们的生命产生巨大影响 了解人类健康和疾病。它还应该导致新的药理学策略 操纵人体时钟以改善时差反应、各种与时钟相关的睡眠和精神疾病的治疗 疾病以及其他人类疾病。了解人类时钟基因和突变将 促进针对衰老、时差反应和其他睡眠障碍的 ASPS 开发更好的疗法。