Circadian and Genetic Evaluation of Extreme Sleep Timing

描述（由申请人提供）：尽管人类喜欢在白天活动，晚上睡觉，但昼夜偏好（“早睡晚睡”）在人群中是高度可变的，受许多因素影响。最近，与中度昼夜偏好相关的昼夜节律性变化已被报道。具有极端昼夜偏好（明确的早晨和晚上类型）的个体通常无法在他们想要的时间睡觉和/或醒来，并且这种睡眠时间与24小时社会和物理环境之间的不一致可能导致昼夜节律睡眠障碍晚期或延迟睡眠阶段综合征（asp， DSPS）。在过去的十年中，昼夜节律的遗传基础已经建立，包括确定构成昼夜节律产生的分子机制的“时钟”基因。由于昼夜节律与昼夜偏好之间的关系，以及动物昼夜节律系统的既定遗传调控，极端的昼夜偏好和昼夜节律睡眠障碍可能存在遗传基础。有报道称昼夜偏好与生物钟基因多态性之间存在关联，也有报道称ASPS和DSPS患者的生物钟基因改变，尽管并非所有研究都同意这一说法。这些差异可能是由于这些研究中使用的表型方法。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，我们提出了一个彻底的表型和遗传评估极端昼夜类型，以确定潜在的时间生物学和人类昼夜偏好的遗传基础，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），使用成熟的方法（恒定的常规和强制的非同步协议）可能会产生不同的表型组，表现出性状样的行为。极端昼型的遗传分析（Specific Aim 4）可以确定时钟基因的相关多态性。这些数据有助于更好地理解极端昼偏好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.