Characterization of familial advanced sleep phase syndrome

家族性睡眠时相提前综合征的特征

• 批准号: 7884499
• 负责人: LOUIS J. PTACEK
• 金额: $ 53.83万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884499
• 关键词: Adult; Advanced Sleep Phase Syndrome; Age; Aging; Alleles; Animal Model; Area; Asthma; Behavior; Behavioral Genetics; Biochemical; Biological; Candidate Disease Gene; Cardiovascular Diseases; Cells; Childhood; Circadian Rhythms; Collection; Coupling; DNA; Delayed Sleep Phase Syndrome; Diet Habits; Disease; Enrollment; Family; Funding; Gene Mutation; Genes; Genetic; Genotype; Grant; Health; Hour; Human; In Vitro; Investigation; Jet Lag Syndrome; Knowledge; Lead; Learning; Life; Light; Link; Malignant Neoplasms; Maps; Measurement; Measures; Mental disorders; Metabolic; Molecular; Molecular Genetics; Mus; Mutation; Nature; Organism; Output; Pattern; Phase; Phase response curves; Phenotype; Physiological; Physiological Processes; Protocols documentation; Psyche structure; Regulation; Resources; Sampling; Sleep; Sleep Disorders Therapy; Sleep Wake Cycle; Strigiformes; System; Testing; Text; Time; Travel; Variant; alertness; autosomal dominant trait; base; circadian pacemaker; genetic linkage analysis; genetic variant; genome-wide linkage; human subject; improved; in vivo; insight; kindred; mouse model; novel; public health relevance; research study; shift work; sleep regulation

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.

描述（由申请人提供）：生物体已经进化出了代谢和生理功能与约24小时的光/暗周期同步的机制。当跨越时区旅行时，我们的睡眠-觉醒模式、精神警觉性、饮食习惯和许多其他生理过程都会暂时受到“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。许多知识来自于对模式生物昼夜节律的遗传和分子基础的研究。尽管生物钟很重要，但探索人类生物钟的机会只有在认识到人类的孟德尔昼夜节律变异（家族性晚期睡眠阶段综合征，FASPS）后才成为可能。在这项资助的初始阶段，我们对FASPS进行了表征，收集了3个家族，并定位和克隆了第一个FASPS基因。在目前的拨款期间，我们已经1)开始识别和收集家族性延迟睡眠阶段综合征（FDSPS）家庭和40个额外的FASPS种类；2)在22个FASPS家族中鉴定出5个新的人类昼夜节律基因和导致FASPS的突变；3)进行体外生化和细胞生物学实验，以了解这些突变的功能后果；4)建立了4个人类昼夜节律基因（Per2、CKId、CKIe和Dec2）中FASPS突变的小鼠模型（并开始表征昼夜节律表型）。在这一竞争性更新中，我们建议扩大我们家族的收集（目标1），确定FDSPS突变（目标2），绘制新的人类昼夜节律位点（目标3），并更详细地表征所有4种FASPS小鼠模型的昼夜节律表型（目标4）。我们还将招募突变阳性的FASPS受试者，以测量周期、相位和相位角。对人类和小鼠的平行研究将协同我们的努力，剖析对人类FASPS的理解，并探索我们的生物钟与其他生物的生物钟之间的异同。研究人类生物钟的分子机制将对我们对人类健康和疾病的理解产生巨大影响，并为药物操纵提供新的策略，以改善时差、各种与生物钟相关的睡眠和精神疾病的治疗。公共卫生相关性：通过对具有强烈的“早起鸟”或“夜猫子”睡眠模式的人类自然发生的突变的研究，我们正在了解人类昼夜节律/睡眠调节的基本机制。这些见解将确定开发更好的治疗睡眠障碍的目标，包括轮班工作和时差。