ACT 3: SLEEP DEPRIVATION STRESS & ENERGY METABOLISM

第三幕：睡眠剥夺压力

• 批准号: 7336129
• 负责人: Michael Koban
• 金额: $ 10.53万
• 依托单位: MORGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7336129
• 关键词: ACT; SLEEP; DEPRIVATION; STRESS; ENERGY

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.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。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。研究人员建议使用斯普拉格-道利大鼠，采用一种有效的应激范例——睡眠剥夺来研究其在多天时间过程中的执行如何导致应激诱发的病理生理学的发展。持续的睡眠不足会导致两个有趣的特征，而使用其他标准压力范式（例如固定或电足电击）则无法观察到这些特征。睡眠不足的动物逐渐增加其能量消耗，因此在应激发生后的几天内，其新陈代谢显着增加。代谢率的升高与明显的食欲亢进同时发生。睡眠不足与能量负平衡有关，体重持续下降就证明了这一点。此外，能量负平衡还伴随着动物进入蛋白质和热量营养不良的状态，而这种状态不能用消化效率下降或糖尿病等消耗性疾病的出现来解释。考虑到这种应激范式及其相关病理学的效力，值得注意的是，人们对所发生的潜在生理和生化变化知之甚少。研究人员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，提出以下工作假设：睡眠不足会导致新陈代谢重组，并且有助于标准代谢率的特定细胞过程显着增加。为了检验这一假设，制定了三个具体目标。目标 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。目标 2 将通过输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是应激引起的 SMR 升高的原因。目标 3 旨在通过确定增加能量耗散的途径，同时关注线粒体质子泄漏，来阐明导致负能量平衡的生化机制。该应用的相关性在于，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，例如能量负平衡的发展、食欲亢进和特殊的内分泌特征。最重要的是，对于当睡眠被剥夺时能量代谢急剧升高的途径和机制几乎一无所知。