SLEEP AND METABOLIC CONSEQUENCES OF CHRONIC PARTIAL SLEEP RESTRICTION IN RATS

大鼠慢性部分睡眠限制的睡眠和代谢后果

• 批准号: 8245079
• 负责人: FRED W TUREK
• 金额: $ 24.08万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8245079
• 关键词: Adipose tissue; Adverse effects; Affect; Age; Age-Months; Aging; Animal Model; Animals; Appetite Depressants; Architecture; Area; Autopsy; Awareness; Behavioral; Biological; Blood specimen; Body mass index; Brain; Cardiovascular Diseases; Cholesterol; Chronic; Circadian Rhythms; Clinical Research; Corticosterone; Data; Development; Diabetes Mellitus; Disease; Doctor of Philosophy; Dose; Elderly; Electroencephalography; Energy Metabolism; Environment; Epidemiologic Studies; Equilibrium; Exhibits; Experimental Animal Model; Fatigue; Frequencies; Funding; Gene Expression; Gene Expression Regulation; Genes; Genetic; Glucocorticoids; Glucose; Glucose tolerance test; Health; Homeostasis; Hormonal; Human; Hypothalamic structure; Inflammatory; Instruction; Insulin; Intervention; Investigation; Lead; Leptin; Life; Link; Liver; Long-Term Effects; Metabolic; Metabolism; Modeling; Molecular; Monitor; Neurosecretory Systems; Nonesterified Fatty Acids; Obesity; Pattern; Peripheral; Phenotype; Physiological; Physiological Processes; Principal Investigator; Procedures; Protocols documentation; REM Sleep; Rattus; Recovery; Regulation; Risk; Rodent; Severities; Signal Transduction; Sleep; Sleep Architecture; Sleep disturbances; Societies; System; Testing; Time; Tissues; Transcript; Triglycerides; Work; age effect; age related; alertness; allostasis; allostatic load; carbohydrate metabolism; circadian pacemaker; coping; cytokine; ghrelin; glucose tolerance; indexing; insight; juvenile animal; lipid metabolism; male; metabolic abnormality assessment; middle age; new technology; novel; novel therapeutics; programs; research study; response; sex; sleep regulation; trait

Seeinstructions): Chronic partial sleep restriction (CPSR) is a hallmark of life in modern human society however, only recently have the consequences of CPSR for chronic human illnesses such as obesity and diabetes come to be fully appreciated. Despite the growing awareness of the importance of sleep as a factor in human health and in the development of age-related diseases, few animal models have been developed to systematically determine how aging effects the consequences of CPSR on the sleep-wake regulatory system itself and on other physiological processes, such as energy metabolism and circadian rhythms. During the previous funding period, we developed a model of CPSR that led to the exciting discovery that after only a few days of CPSR, both young and old rats no longer exhibited a homeostatically regulated sleep recovery pattern; they failed to generate increases in NREM EEG delta power and NREM sleep time. In addition, we demonstrated an impact of CPSR on leptin and glucocorticoid concentrations, glucose tolerance, and insulin responsiveness in young rats. These data led us postulate a novel hypothesis that repeated episodes of sleep restriction result in the transition from a homeostatic to an allostatic state of sleep regulation that may lead to adaptive changes in the sleep-wake and other physiological systems to cope with the immediate environmental challenge inducing sleep loss. However, such initially adative changes could have adverse effects if the allostatic response to CPSR is maintained for a prolonged period of time. In the proposed studies, we will systematically examine this working model in two Specific Aims (1) Test the hypothesis that aging accelerates the transition from homeostatis to allostasis during CPSR. Specifically, we will determine if aging impacts the severity and duration of sleep restriction necessary to cause the transition from a homeostatic to an allostatic sleep regulatory state (2) Test the hypothesis that aging alters the effects of CPSR on key hormonal and molecular components of energy metabolism and circadian clock gene expression in the CMS and peripheral tissues, and that the adverse effects of CPSR on metabolism are a consequence and are exacerbated by the transition from a homeostatic to an allostatic sleep regulatory state RELEVANCE (See instructions): The use of an animal model to determine the effects of chronic partial sleep restriction (CPSR) and how aging impacts the response to CPSR, is expected to lead to new insights into the biological mechanisms that link short sleep in humans with cardiometabolic diseases, and new therapeutic strategies for treating age- related metabolic and associated disorders, such as obesity, diabetes, and cardiovascular disease.

参见说明）： 慢性部分睡眠限制（CPSR）是现代人类社会生活的一个标志，然而直到最近 CPSR 对肥胖和糖尿病等慢性人类疾病的影响已得到充分体现 赞赏。尽管人们越来越认识到睡眠作为人类健康的一个因素的重要性， 与年龄相关疾病的发展，很少有动物模型能够系统地开发 确定衰老如何影响 CPSR 对睡眠-觉醒调节系统本身和 其他生理过程，例如能量代谢和昼夜节律。此前期间 在资助期间，我们开发了一个 CPSR 模型，该模型带来了令人兴奋的发现：仅经过几天的研究 CPSR，年轻和年老的大鼠都不再表现出稳态调节的睡眠恢复模式；他们 未能增加 NREM 脑电图增量功率和 NREM 睡眠时间。此外，我们还展示了 CPSR 对瘦素和糖皮质激素浓度、葡萄糖耐量和胰岛素的影响 年轻大鼠的反应能力。这些数据使我们提出了一个新的假设，即重复发生的事件 睡眠限制导致睡眠调节从稳态过渡到非稳态状态，这可能 导致睡眠-觉醒和其他生理系统的适应性变化，以应对眼前的情况 环境挑战导致睡眠不足。然而，这种最初的适应性改变可能会产生不利的影响 如果对 CPSR 的变稳态反应维持较长时间，就会产生影响。在提议的 研究中，我们将在两个具体目标中系统地检验这个工作模型 (1) 检验假设 衰老加速了 CPSR 期间从稳态到失稳态的转变。具体来说，我们将确定是否 衰老会影响睡眠限制的严重程度和持续时间，而睡眠限制是导致从睡眠状态转变所必需的。 稳态到非稳态睡眠调节状态 (2) 检验衰老会改变睡眠调节效果的假设 CPSR 对能量代谢和生物钟基因的关键激素和分子成分的影响 CMS 和外周组织中的表达，并且 CPSR 对代谢的不利影响是 后果，并因从稳态睡眠调节状态转变为非稳态睡眠调节状态而加剧 相关性（参见说明）： 使用动物模型来确定慢性部分睡眠限制 (CPSR) 的影响以及如何 衰老影响对 CPSR 的反应，预计将带来对生物机制的新见解 将人类睡眠不足与心脏代谢疾病联系起来，以及治疗年龄相关的新治疗策略 相关的代谢和相关疾病，例如肥胖、糖尿病和心血管疾病。