Circadian & Genetic Evaluation of Extreme Sleep Timing

描述(申请人提供)：虽然人类更喜欢白天活动，晚上睡觉，但白天的偏好(早晚)在人群中变化很大，受到许多因素的影响。最近，有报道称，昼夜节律性的变化与适度的昼夜偏好有关。具有极端昼夜偏好的人(明确的早晚类型)通常无法在他们想要的时间入睡和/或醒来，这种睡眠时间与24小时社会和物理环境之间的错位可能导致昼夜节律睡眠障碍晚期或延迟睡眠相综合症(ASPS，DSSPS)。在过去的十年里，昼夜节律的遗传基础已经得到了很好的证实，包括鉴定构成昼夜节律产生的分子机制的“时钟”基因。由于昼夜节律和昼夜节律之间的关系，以及动物昼夜节律系统的遗传调控，极端的昼夜偏爱和昼夜节律睡眠障碍可能有遗传基础。虽然不是所有的研究都同意这一点，但也有关于昼夜偏爱与时钟基因多态之间的关系的报道，以及关于ASPS和DSS患者时钟基因改变的报道。这些差异可能是由于这些研究中使用的表型方法所致。关于这些表型的时间生物学和睡眠机制以及遗传基础，仍有许多未知之处。在这里，我们建议对极端昼夜类型进行彻底的表型和遗传学评估，以确定人类昼夜喜好的潜在时间生物学和遗传学基础，从而将特定基因与可观察到的行为联系起来。仔细评估内源性昼夜节律阶段(特定目标1)、周期(特定目标2)和睡眠倾向模式(特定目标3)，使用公认的方法(固定例程和强制去同步法)，可能会产生表现出特征样行为的不同表型组？对极端昼夜节律类型的遗传分析(特定目标4)可能识别时钟基因的相关多态。这些数据应该可以更好地理解极端昼夜偏爱的时间生物学和遗传学基础，从而更好地治疗昼夜节律睡眠障碍。

DESCRIPTION (provided by applicant): Although humans prefer to be active during the day and to sleep at night, diurnal preference ("morningness-eveningness") is highly variable in the population and influenced by many factors. Recently, variations in circadian rhythmicity associated with moderate diurnal preference have been reported. Individuals with extreme diurnal preference (definite morning and evening types) often have an inability to sleep and/or wake at their desired times, and such misalignment between sleep timing and the 24-h social and physical environment can lead to the circadian rhythm sleep disorders Advanced or Delayed Sleep Phase Syndrome (ASPS, DSPS). In the past decade, the genetic basis of circadian rhythmicity has been well-established, including identification of "clock" genes that comprise the molecular mechanism for the generation of circadian rhythms. Because of the relationship between circadian rhythms and diurnal preference, and the established genetic regulation of the circadian system in animals, there is likely to be a genetic basis to extreme diurnal preference and the circadian rhythm sleep disorders. There are reports of associations between diurnal preference and polymorphisms in clock genes, and reports of clock gene alterations in patients with ASPS and DSPS, although not all studies agree. These discrepancies may be due to the phenotyping methods used in those studies. Much remains unknown about the chronobiologic and sleep mechanisms, as well as the genetic basis, of these phenotypes. Here we propose a thorough phenotypic and genetic evaluation of extreme diurnal types to determine the underlying chronobiologic and genetic basis of human diurnal preference, thereby linking specific genes with observable behavior. A careful evaluation of the endogenous circadian phase (Specific Aim 1), period (Specific Aim 2), and pattern of sleep propensity (Specific Aim 3), using well-established methods (constant routine and forced desynchrony protocols) is likely to yield distinct phenotypic groups exhibiting trait-like behaviors? Genetic analysis of extreme diurnal types (Specific Aim 4) may identify associated polymorphisms in clock genes. These data should provide better understanding of the chronobiologic and genetic basis of extreme diurnal preference, leading to better treatments for circadian rhythm sleep disorders.