Bmal1 as a Central and Peripheral Regulator of Sleep Homeostasis

描述(申请人提供)：睡眠不足是一个普遍的公共卫生问题，它增加了新陈代谢需求和随后相关的发病率和死亡率风险。为了更好地了解睡眠不足的恢复机制和睡眠不足的后果，本培训计划旨在从神经化学、生理和细胞水平研究中枢和外周分子(BMAL1)对睡眠和新陈代谢的调节。BMal1是一个中心焦点，因为它是一种昼夜节律转录因子，被认为影响日常睡眠数量和从睡眠缺失中恢复。这项研究提案的具体目标将通过使用具有脑部或骨骼肌特异性BMAL1表达扩增或挽救的转基因小鼠来实现。在这些小鼠中使用四环素反式激活系统还可以暂时抑制或挽救组织特异性BMAL1的表达，以便区分发育和直接影响之间的关系。中心假设是，在睡眠缺失期间，中枢和外周代谢需求的增加程度取决于基底前脑中细胞外腺苷和骨骼肌中葡萄糖和氧气的利用水平，而这些参数在恢复睡眠期间的分散程度取决于组织特异性BMAL1的表达。这些信息将促进我们的科学理解，并解决BMAL1在睡眠缺失期间如何以及在哪里影响睡眠和代谢过程的关键障碍。这一中心假设的实施需要综合过去、现在和提出的研究方法、培训和与我的赞助人的有效沟通，他们是睡眠、昼夜节律和骨骼肌生理学领域的专家。具体目标还将辅之以合作研究项目、继续教育和教学，这些项目将提供代谢、神经生理学和分子研究方法以及专业发展方面的额外培训。

DESCRIPTION (provided by applicant): Insufficient sleep is a widespread public health problem that increases metabolic demands and subsequent related risks of morbidity and mortality. To better understand the mechanisms of recovery from insufficient sleep and the consequences of insufficient sleep, this training plan aims to examine central and peripheral molecular (BMAL1) regulation of sleep and metabolism at neurochemical, physiological, and cellular levels. BMAL1 is a central focus because it is a circadian transcription factor that is thought to influence daily sleep amount and recovery from sleep loss. The specific aims of this research proposal will be addressed by the use of transgenic mice that have amplification or rescue of BMAL1 expression specific to the brain or skeletal muscle. Use of the tetracycline transactivator system in these mice also permits for temporal knockdown or rescue of tissue-specific BMAL1 expression in order to delineate between developmental versus direct effects. The central hypothesis is that the extent of increases in central and peripheral metabolic demands during sleep loss, determined from levels of extracellular adenosine in the basal forebrain and glucose and oxygen utilization in skeletal muscle, and the extent of dissipations of these parameters during recovery sleep is dependent on tissue-specific BMAL1 expression. This information will advance our scientific understanding and resolve critical barriers of how and where BMAL1 influences sleep and metabolic processes during sleep loss. The execution of this central hypothesis requires a synthesis of past, present, and proposed research methods training and effective communication with my sponsors, who are experts in areas of sleep, circadian rhythms, and skeletal muscle physiology. The specific aims will also be supplemented with collaborative research projects, continued education, and teaching, which will provide additional training in metabolic, neurophysiological, and molecular research methods and professional development.