Characterization of Familial Advanced Sleep Phase Syndrome

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的后果， 异相 直到我们适应 新的时区。此外，最近的研究还将生物钟的破坏与许多 疾病，包括：哮喘、癌症、心血管疾病和学习障碍。渊博的知识 来自于研究模式生物中昼夜节律的遗传和分子基础。尽管 生物钟对我们生理和行为的各个方面的重要性，有机会探索 人类生物钟只有在人类中识别出孟德尔昼夜节律变异后才成为可能 （家族性晚期睡眠相，familial advanced sleep phase，FASP）。在此赠款的前几个资助期内，我们描述了FASP， 收集了多个家系，并定位和克隆了第一个FASP基因。我们接着确定了总共5个FASP 基因，并建立了所有这些基因的动物模型。我们还描述了家族性自然短睡眠 （FNSS）并克隆了第一个人类睡眠基因/突变。在当前的拨款期间，我们ve 1） 在描述昼夜节律激酶CKI <$、CKI <$和GSK 3 <$的蛋白质组学方面做了大量工作; 2） 鉴定了导致FASP的TIP 2和TIMELESS中的突变，并生成了小鼠模型; 3） 表征了PKC在食物可消化振荡器中的作用; 4）证明了昼夜节律 CKI的突变也会导致有先兆的偏头痛。在这次竞争性更新中，我们建议收集 额外的家庭（目标1），在50岁以下的先证者中进行全外显子组测序 不明原因 FASP 家族（目的2），并在许多变体中筛选以鉴定新的昼夜节律/FASP基因/突变 (Aim 3）。在人类和小鼠模型中的平行研究将协同解剖理解FASP， 人类和探索我们的生物钟与其他生物钟之间的相似性和差异 有机体研究人类昼夜节律的分子机制将产生巨大的影响 我们对人类健康和疾病的理解。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。

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, recent studies have also linked disruption of the circadian clock with numerous ailments, including: asthma, cancer, cardiovascular 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). In the previous funding periods of this grant, we characterized FASP, collected many families, and mapped and cloned the first FASP gene. We went on to identify a total of 5 FASP genes and have generated animal models of all of them. We also described Familial Natural Short Sleep (FNSS) and have cloned the first human sleep gene/mutation. During the current grant period, weve 1) done extensive work in characterizing the proteomics of circadian kinases CKI¿, CKI¿, and GSK3¿; 2) identified mutations in CRY2 and TIMELESS causing FASP and generated mouse models; 3) characterized the role of PKC¿ in the food entrainable oscillator; 4) Demonstrated that circadian mutations in CKI¿ also cause migraine with aura. In this competitive renewal, we propose to collect additional families (Aim 1), to perform whole exome sequencing in probands from 50 unexplained FASP families (Aim 2), and to sift among the many variants to identify novel circadian rhythm/FASP genes/mutations (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.