ACT 3: SLEEP DEPRIVATION STRESS & ENERGY METABOLISM

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。该实验室的长期目标是更好地了解哺乳动物应对压力的生理和生化机制。使用Sprague-Dawley大鼠，研究人员提出采用有效的应激范式，即睡眠剥夺来研究其在许多天的时间过程中的实施如何导致应激诱导的病理生理学的发展。持续的睡眠缺失导致两个有趣的特征，这是使用其他标准压力范例（如固定或电击脚）无法观察到的。睡眠剥夺的动物逐渐增加其能量消耗，使得在应激开始的几天内，其代谢显著增加。这种代谢率的升高与明显的摄食过多相一致。睡眠剥夺与负能量平衡有关，体重持续下降就是证明。此外，负能量平衡伴随着动物进入蛋白质和热量营养不良的状态，这不能用消化效率下降或糖尿病等消耗性疾病的发病来解释。考虑到这种压力模式及其相关病理学的潜力，值得注意的是，更多的是不知道发生的潜在生理和生化变化。研究者的目的是剖析这些属性的要素，以进一步了解睡眠剥夺相关的病理生理学。因此，提出了以下工作假设：睡眠剥夺导致新陈代谢的重组，并且有助于标准代谢率的特定细胞过程显着增加。为了验证这一假设，已经制定了三个具体目标。目的1是通过测量O2消耗和CO2产生来确定应激引起的整个动物标准代谢率（SMR）变化的时间过程。目的2将通过灌注放射性核素标记的微球来测量组织血流的变化，从而确定哪些组织和器官负责应激诱导的SMR升高。目标3旨在通过确定增加能量耗散的途径来阐明负能量平衡发展的生化机制，同时关注线粒体质子泄漏。这一应用的相关性在于，睡眠剥夺不符合通常的压力范式，因为它具有相当常见的特征，如负能量平衡的发展、暴食和特殊的内分泌特征。最重要的是，几乎没有人知道能量代谢的途径和机制，当睡眠被剥夺时，能量代谢会强烈升高。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term goal of this laboratory is to better understand the physiological and biochemical mechanisms by which mammals respond to stress. Using Sprague-Dawley rats, the investigators propose to employ a potent stress paradigm, sleep deprivation to investigate how its enforcement over a time course of many days results in the development of stress- induced pathophysiology. Sustained loss of sleep results in two interesting features that are not observed using other standard stress paradigms such as immobilization or electric foot shock. The sleep deprived animal progressively increases its energy expenditure so that within days of onset of the stress, its metabolism increases significantly. This elevation in metabolic rate is coincident with pronounced hyperphagia. Sleep denial is associated with a negative energy balance, as evidenced by steady loss in body weight. In addition, the negative energy balance is accompanied by the animal entering a state of protein and caloric malnutrition that cannot be explained by declines in digestive efficiency, or nascence of wasting diseases such as diabetes. Given the potency of this stress paradigm and its associated pathologies, it is remarkable is that more is not known about the underlying physiological and biochemical changes that occur. It is the intent of the investigators to dissect elements of these attributes to further understanding of sleep deprivation associated pathophysiology. Therefore, the following working hypothesis is proposed: that sleep deprivation causes a reorganization of metabolism, and that specific cellular processes contributing to standard metabolic rate become markedly increased. To test this hypothesis, three Specific Aims have been developed. Aim 1 is to determine the time course of stress-induced changes in whole animal standard metabolic rate (SMR) by measuring O2 consumption and CO2 production. Aim 2 will establish which tissues and organs are responsible for stress induced elevation of SMR by measuring changes in tissue blood flow via infusion of radionuclide labeled microspheres. Aim 3 seeks to elucidate the biochemical mechanisms responsible for the developing negative energy balance by determining avenues for increased energy dissipation, while focusing on mitochondrial proton leakage. The relevance of this application is that sleep deprivation does not fit the usual stress paradigm because of its rather usual characteristics such as development of negative energy balance, hyperphagia, and peculiar endocrine profiles. Most importantly, practically nothing is known about the pathways and mechanisms of energy metabolism that become strongly elevated as sleep is denied.