Characterization of familial advanced sleep phase syndrome

描述(申请人提供)：生物体已经进化出机制，使代谢和生理功能与~24小时的光/暗周期同步。当我们跨时区旅行时，我们的睡眠-觉醒模式、精神警觉性、饮食习惯和许多其他生理过程暂时会受到“不同步”的影响，直到我们适应新的时区。此外，最近的研究还将生物钟的紊乱与许多疾病联系起来，包括：哮喘、癌症和心血管疾病。在模型生物中研究昼夜节律的遗传和分子基础已经获得了许多知识。尽管生物钟很重要，但只有在人们认识到孟德尔式昼夜节律变异(家族性晚期睡眠相综合征，FASPS)的情况下，才有可能探测到人类的生物钟。在这笔赠款的初始资助期间，我们对FASPS进行了鉴定，收集了3个家系，并定位和克隆了第一个FASPS基因。在当前的资助期内，我们已经1)开始识别和收集家族性睡眠延迟综合征(FDSPS)家系和40个额外的FASPS家系；2)在我们的前22个FASPS家族中发现了5个新的人类昼夜节律基因和导致FASPS的突变；3)进行了体外生化和细胞生物学实验，以了解这些突变的功能后果；以及4)建立了4个人类昼夜节律基因(PER2、CKiD、CKIE和Dec2)的FASPS突变的小鼠模型(并开始表征其昼夜表型)。在这一竞争性更新中，我们建议扩大我们的家系集合(目标1)，鉴定FDSPS突变(目标2)，从基因上定位新的人类昼夜节律基因座(目标3)，并更详细地表征所有4个FASPS小鼠模型的昼夜节律表型(目标4)。我们还将把突变阳性的FASPS受试者纳入一项测量周期、相位和相位角的方案。在人类和小鼠身上进行的平行研究将有助于我们努力剖析人类对FASPS的理解，并探索我们的生物钟与其他生物体之间的异同。研究人体时钟的分子机制将对我们理解人类的健康和疾病产生巨大的影响，并导致新的药物操纵策略来改善时差、各种与时钟相关的睡眠和精神障碍的治疗。与公共卫生相关：通过研究具有强烈的早起云雀或夜猫子睡眠模式的人类自然发生的突变，我们正在了解人类昼夜节律/睡眠调节的基本机制。这些见解将为开发更好的睡眠障碍治疗方法确定目标，包括轮班工作和时差反应。

DESCRIPTION (provided by applicant): Living organisms have evolved mechanisms to synchronize metabolic and physiological functions with the ~24 hour light/dark cycle. 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, and cardiovascular diseases. Much knowledge has come from studying the genetic and molecular basis of circadian rhythms in model organisms. Despite the importance of the circadian clock, the opportunity to probe the human circadian clock only became possible with the recognition of a Mendelian circadian variant in people (familial advanced sleep-phase syndrome, FASPS). In the initial funding period of this grant, we characterized FASPS, collected 3 families, and mapped and cloned the first FASPS gene. During the current grant period, we've 1) begun to identify and collect familial delayed sleep phase syndrome (FDSPS) families and >40 additional FASPS kindreds; 2) identified 5 novel human circadian rhythm genes and mutations causing FASPS in our first 22 FASPS families; 3) performed in vitro biochemical and cell biological experiments to understand functional consequences of these mutations; and 4) generated mouse models (and begun to characterize circadian phenotypes) of FASPS mutations in 4 human circadian rhythm genes (Per2, CKId, CKIe, and Dec2). In this competitive renewal, we propose to expand collection of our families (Aim 1), to identify FDSPS mutations (Aim 2), to genetically map novel human circadian rhythm loci (Aim 3), and to characterize circadian phenotypes of all 4 FASPS mouse models in greater detail (Aim 4). We will also enroll mutation positive FASPS subjects into a protocol to measure period, phase, and phase angles. Parallel studies in humans and mice will synergize in our efforts to dissect understanding of FASPS in humans and exploring the similarities and differences between our clocks vs. those of other organisms. Studying the molecular mechanism of human clock will have an enormous impact on our understanding of human health & disease and lead to new strategies for pharmacological manipulation to improve the treatment of jetlag, various clock-related sleep and psychiatric disorders. PUBLIC HEALTH RELEVANCE: Through study of naturally occurring mutations in humans with strong 'morning lark' or 'night owl' sleep wake patterns, we are learning about basic mechanisms of human circadian/sleep regulation. Such insights will identify targets for developing better therapies for sleep disorders including shift work and jetlag.