Bmal1 as a Central and Peripheral Regulator of Sleep Homeostasis

描述（由申请人提供）：睡眠不足是一个普遍存在的公共卫生问题，它会增加代谢需求和随后的相关发病率和死亡率风险。为了更好地了解从睡眠不足中恢复的机制和睡眠不足的后果，本训练计划旨在研究中枢和外周分子（BMAL1）在神经化学、生理和细胞水平上对睡眠和代谢的调节。BMAL1是一个中心焦点，因为它是一个昼夜节律转录因子，被认为影响每天的睡眠量和从睡眠不足中恢复。这项研究计划的具体目的将通过使用转基因小鼠来解决，这些小鼠具有扩增或挽救脑或骨骼肌特异性BMAL1表达的能力。在这些小鼠中使用四环素反激活剂系统也允许暂时敲低或挽救组织特异性BMAL1表达，以便描述发育与直接影响之间的关系。核心假设是，睡眠缺失期间中枢和外周代谢需求的增加程度（由基底前脑细胞外腺苷水平和骨骼肌葡萄糖和氧气利用水平决定），以及这些参数在恢复性睡眠期间的消散程度取决于组织特异性BMAL1表达。这一信息将促进我们的科学理解，并解决BMAL1如何以及在何处影响睡眠和睡眠缺失期间的代谢过程的关键障碍。执行这一中心假设需要综合过去，现在和建议的研究方法，训练和与我的赞助者的有效沟通，他们是睡眠，昼夜节律和骨骼肌生理学领域的专家。具体目标还将辅以合作研究项目、继续教育和教学，这将提供代谢、神经生理学和分子研究方法和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.