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时间，影响了驱动系统 睡眠和清醒之间的日常互动关系。不幸的是，生理的，神经的， 这些系统的基因组成在很大程度上仍未确定。基因和基因的鉴定 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。由于两国之间的相互关系 睡眠和清醒是由1)昼夜节律系统和2)分配给 睡眠量作为之前唤醒持续时间的函数，这是两个系统共享共同的原因 分子元素。本提案中描述的实验将利用最近生成的 条件转基因小鼠品系，以检验Bmall，昼夜节律的核心组成部分的假设 计时系统，促进清醒，支持对失眠的动态平衡反应。具体目标1 将决定Bmall表达的放大是增强觉醒还是改变体内平衡 通过多导睡眠图分析转基因小鼠的睡眠-觉醒状态对睡眠缺失的反应 过度表达Bmall，但保留昼夜节律功能。具体目标2将确定影响在哪里 Bmall对睡眠-觉醒周期的影响是通过检测转基因小鼠的睡眠-觉醒状态来调节的 它只在大脑或外周表达Bmall。具体目标3将决定是否影响 睡眠-觉醒状态的改变是由突变的发育影响直接驱动或诱导的。 这将通过检测转基因小鼠的睡眠唤醒状态来完成，转基因小鼠的Bmall在 脑组织将有条件地被多西环素激活和失活。这些项目的目标是 研究的目的是建立和表征昼夜节律系统和生物钟之间的分子联系 驱动睡眠和/或清醒的过程。通过使用新的转基因技术，这项研究将 允许分析睡眠期间对基因表达的时间和空间操纵以检查 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.