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: 8282728
• 负责人: LOUIS J. PTACEK
• 金额: $ 53.14万
• 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/8282728
• 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; 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; 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）：生物体已经进化出使代谢和生理功能与~24小时光/暗周期同步的机制。当穿越时区旅行时，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暂时遭受“异相”的后果，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联系起来，包括：哮喘，癌症和心血管疾病。许多知识来自于研究模式生物中昼夜节律的遗传和分子基础。尽管生物钟很重要，但只有在人们认识到孟德尔昼夜节律变异（家族性晚期睡眠阶段综合征，FASPS）后，才有可能探测人类生物钟。在该基金的最初资助期间，我们描述了FASPS，收集了3个家庭，并定位和克隆了第一个FASPS基因。在目前的资助期间，我们已经1）开始鉴定和收集家族性睡眠时相延迟综合征（FDSPS）家族和超过40个额外的FASPS激酶; 2）在我们的前22个FASPS家族中鉴定了5个新的引起FASPS的人类昼夜节律基因和突变; 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;和4）产生4种人昼夜节律基因（Per 2、CKId、CKIe和Dec 2）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），鉴定FDSPS突变（目标2），遗传学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种FASPS小鼠模型的昼夜节律表型（目标4）。我们还将在方案中招募突变阳性FASPS受试者，以测量周期、相位和相位角。在人类和小鼠中进行的平行研究将有助于我们深入了解人类的FASPS，并探索我们的生物钟与其他生物钟之间的相似性和差异。研究人类生物钟的分子机制将对我们理解人类健康和疾病产生巨大影响，并导致新的药理学操作策略，以改善时差反应，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：通过研究具有强烈的“早晨百灵鸟”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疗法（包括轮班工作和时差）确定目标。

项目成果

Diagnostic and management approach to common sleep disorders during pregnancy.

怀孕期间常见睡眠障碍的诊断和管理方法。

• DOI: 10.1097/grf.0b013e31828f2717
• 发表时间: 2013
• 期刊: Clinical obstetrics and gynecology
• 影响因子: 1.5
• 作者: Jones,ChristopherR

Genetic approaches to human behavior.

• DOI: 10.1016/s0076-6879(05)93009-7
• 发表时间: 2005
• 期刊: Methods in enzymology
• 作者: L. Ptáček;Christopher R. Jones;Ying-Hui Fu

Nuclear envelope protein MAN1 regulates clock through BMAL1.

• DOI: 10.7554/elife.02981
• 发表时间: 2014-09-02
• 期刊: eLife
• 影响因子: 7.7
• 作者: Lin ST;Zhang L;Lin X;Zhang LC;Garcia VE;Tsai CW;Ptáček L;Fu YH
• 通讯作者: Fu YH

Casein kinase iδ mutations in familial migraine and advanced sleep phase.

• DOI: 10.1126/scitranslmed.3005784
• 发表时间: 2013-05-01
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Brennan KC;Bates EA;Shapiro RE;Zyuzin J;Hallows WC;Huang Y;Lee HY;Jones CR;Fu YH;Charles AC;Ptáček LJ
• 通讯作者: Ptáček LJ

Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock.

• DOI: 10.1016/j.cmet.2012.12.017
• 发表时间: 2013-02-05
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Kaasik K;Kivimäe S;Allen JJ;Chalkley RJ;Huang Y;Baer K;Kissel H;Burlingame AL;Shokat KM;Ptáček LJ;Fu YH
• 通讯作者: Fu YH