Bmal1: a potential homeostatic regulator of the sleep-wake cycle

睡眠障碍和环境挑战减少了每天的睡眠量， 睡眠和清醒之间的日常相互关系。不幸的是，生理的，神经的， 这些系统的遗传组成在很大程度上仍不确定。基因的鉴定和 驱动和响应每日睡眠-觉醒量变化的分子将提供新的治疗靶点 用于治疗睡眠障碍和共病状态。由于相互之间的关系 睡眠和觉醒是由1）昼夜节律计时系统和2）分配 作为先前唤醒持续时间的函数的睡眠量，这两个系统共享共同的 分子元素本提案中描述的实验将利用最近生成的 条件性转基因小鼠的品系来检验Bmall，昼夜节律的核心成分， 定时系统，促进觉醒和支持对睡眠不足的自我平衡反应。具体目标1 将决定Bmall表达的扩增是否会增强觉醒或改变体内平衡， 通过多导睡眠图分析转基因小鼠品系的睡眠-觉醒状态， 过表达Bmall但保留昼夜节律功能。具体目标2将确定影响 Bmall对睡眠-觉醒周期的影响是通过检查转基因小鼠品系的睡眠-觉醒状态来介导的 只在大脑或周围表达Bmall。具体目标3将决定 Bmall对睡眠-觉醒状态的影响是直接驱动的或通过突变的发育影响诱导的。 这将通过检查转基因小鼠的睡眠-觉醒状态来实现，所述转基因小鼠的Bmall表达在 脑组织将被多西环素给药条件性激活和失活。这些目标 研究的目的是建立和表征昼夜节律计时系统和生物钟之间的分子联系。 驱动睡眠和/或觉醒的过程。通过使用新的转基因技术，这项研究将 允许在基因表达的时间和空间操作期间分析睡眠， 治疗睡眠障碍的潜在治疗靶点。

Sleep disorders and environmental challenges that reduce daily sleep amount act upon systems that drive the daily reciprocal relationship between sleep and wakefulness. Unfortunately, the physiological, neural, and genetic composition of these systems remains largely undetermined. The identification of the genes and molecules that drive and respond to changes in daily sleep-wake amount will provide new therapeutic targets for the treament of sleep disorders and co-morbid disease states. Since the reciprocal relationship between sleep and wakefulness is driven by 1) the circadian timing system and 2) a homeostatic system that allots sleep amount as a function of prior wake duration, it stands to reason that the two systems share common molecular elements. The experiments described in this proposal will take advantage of recently generated lines of conditional transgenic mice to test the hypothesis that Bmall, a core component of the circadian timing system, facilitates wakefulness and bolsters the homeostatic response to sleep loss. Specific aim 1 will determine whether amplication of Bmall expression enhances wakefulness or modifies the homeostatic response to sleep loss by polysomnographically analyzing sleep-wake states in a transgenic mouse line that over-expresses Bmall but conserves circadian function. Specific aim 2 will determine where the influences of Bmall on the sleep-wake cycle are mediated by examining sleep-wake states in transgenic mouse lines that exclusively express Bmall in the brain or periphery. Specific aim 3 will determine whether influences of Bmall on sleep-wake states are driven directly or induced through developmental influences of the mutation. This will be accomplished by examining sleep-wake states in transgenic mice whose expression of Bmall in brain tissue will be conditionally activated and deactivated by doxycycline administration. The goal of these studies is to establish and characterize a molecular link between the circadian timing system and the processes that drive sleep and/or wakefulness. Through the use of new trangenic technology this study will allow the analysis of sleep during the temporal and spatial manipulation of gene expression to examine potential therapeutic targets for treatment of sleep disroders.