AN INTERDISCIPLINARY STUDY OF DELAYED SLEEP PHASE DISORDER

描述（由申请人提供）：昼夜节律睡眠障碍占失眠诊断病例的15%，其中延迟睡眠阶段障碍（DSPD）占此类病例的绝大多数。这些睡眠阶段障碍的诊断和治疗受到解决这些障碍的关键方面的数据的显著缺乏的阻碍，包括缺乏充分表征睡眠障碍本身的研究。DSPD的病理生理学在很大程度上仍停留在理论层面，这也是由于缺乏相关数据。昼夜节律睡眠障碍遗传标记识别的进展，结合研究人类睡眠和生物节律的既定方法，为昼夜节律睡眠障碍的研究提供了令人兴奋的途径。这项研究的目的是使用跨学科的方法来提高我们对这种疾病的理解，以及对正常睡眠调节的理解。我们将检验以下假设：被诊断为DSPD的个体将表现出1)自发周期长度（tau）明显长于正常对照；2)睡眠与体温的相位关系改变导致睡眠质量下降；3)一个或多个标准时钟基因的变异以及异常分子tau。最后，我们假设在两组（DSPD和正常对照组）中，tau的行为（睡眠/清醒，活动记录）和生理（体温，褪黑激素）测量将与tau的分子测量呈正相关。40名受试者（20名诊断为DSPD， 20名正常对照）将接受一项由携带和“自由运行”组成的实验室方案，在此期间，睡眠和昼夜节律变量被连续记录。通过使用RT-PCR技术跟踪时钟位点的节律性表达，并通过分析生物钟驱动的荧光素酶报告基因的表达，将在源自成纤维细胞的细胞培养物中测量“分子”tau。分析将集中在DSPD和正常对照之间tau的假设差异，DSPD的睡眠特征，睡眠质量和昼夜节律相角之间的关系，以及在行为、生理和分子水平上评估的昼夜节律测量之间的假设关系。这项工作将是第一次使用这样的跨学科方法来更好地表征和理解行为和生理水平上的正常和病理昼夜节律睡眠调节，同时获得对人类睡眠/觉醒系统昼夜节律时间基础的遗传学的重要见解。

DESCRIPTION (provided by applicant): Circadian rhythm sleep disorders constitute up to 15% of diagnosed cases of insomnia, with Delayed Sleep Phase Disorder (DSPD) representing a large majority of such cases. Diagnosis and treatment of these sleep phase disturbances are hampered by a remarkable paucity of data addressing key aspects of the disorders, including a virtual absence of studies that adequately characterize the sleep disturbance, itself. The pathophysiology underlying DSPD remains largely theoretical in scope, due also to a lack of data shedding light on this issue. Advances in the identification of genetic markers for circadian rhythm sleep disorders, combined with established methods for studying human sleep and biological rhythms, offer exciting avenues in the study of circadian rhythm sleep disorders. The aim of this study is to use an interdisciplinary approach to enhance our understanding of such disorders, and that of normal sleep regulation. We will test the hypotheses that individuals diagnosed with DSPD will exhibit 1) spontaneous period lengths (tau) that are significantly longer than normal controls; 2) altered phase relationships between sleep and body temperature that contribute to reduced sleep quality; 3) variations in one or more of the canonical clock genes as well as aberrant molecular tau. Finally, we hypothesize that across both groups (DSPD and normal controls), behavioral (sleep/wake, actigraphy) and physiological (body temperature, melatonin) measurements of tau will be positively correlated with molecular measurements of tau. Forty subjects (20 diagnosed with DSPD, 20 normal controls) will undergo a laboratory protocol consisting of entrained and "free-run" components, during which sleep and circadian variables are continuously recorded. 'Molecular' tau will be measured in cell cultures derived from fibroblasts, by tracking rhythmic expression of clock loci using RT-PCR techniques, and by analyzing the expression of a circadian clock-driven luciferase reporter. Analyses will focus on hypothesized differences in tau between DSPD, and normal controls, on the characterization of sleep in DSPD, on examination of the relationships between sleep quality and circadian phase-angle, and on the examination of hypothesized relationships among circadian measures assessed at the behavioral, physiologic and molecular levels. This work will be the first to use such an interdisciplinary approach to better characterize and understand normal and pathological circadian sleep regulation at the behavioral and physiological levels, while gaining important insights into the genetics that underlie circadian timing of the human sleep/wake system.