Probing genetics and biology of human circadian function

摘要 在地球上，生物体进化出同步新陈代谢和生理功能的机制。 有大约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。当跨越时区旅行时，我们的睡眠-唤醒模式、精神警觉性、饮食习惯以及许多 其他生理过程暂时遭受“不同步”的后果，直到我们适应 新的时区。此外，很大一部分人口正在进行墓地轮班，其中包括 医护人员、警察、卡车司机和工厂工人。最近的研究表明， 有许多疾病的生物钟，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。大量的知识来自于对 模式生物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方方面面，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识别(家族性晚期睡眠阶段， FASP)。我们对FASP进行了鉴定，收集了多个家系，并定位和克隆了第一个FASP基因。我们 接着鉴定了总共6个FASP基因，并建立了所有这些基因的动物模型。尽管如此，一个大的 大多数FASP家族在已知的时钟基因上没有突变。在这份提案中，我们概述了一项计划 继续收集更多的家系(目标1)，对来自&gt；50的先证者进行完整的外显子组测序 无法解释的FASP家族，并在变种中筛选以确定新的昼夜节律/FASP 基因/突变(目标2)。最后，由于最初的1-2年将集中在识别新的FASP基因上，我们 建议对永恒基因中的人类FASP突变进行体外和体内研究(目标3)。 在人类和小鼠模型上的平行研究将在剖析人类对FASP的理解方面发挥协同作用 并探索我们的生物钟与其他生物体的生物钟之间的异同。 研究人类昼夜节律的分子机制将对我们的生活产生巨大的影响 对人类健康和疾病的了解。它还应该导致新的药理学策略 操控人体时钟改善时差、各种时钟相关睡眠和精神疾病 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 能够开发更好的治疗衰老、时差和其他睡眠障碍的ASPS的方法。

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.