IMPACT OF SLEEP LOSS AND CIRCADIAN DISRUPTION ON NEURAL REGULATION OF METABOLISM

睡眠不足和昼夜节律紊乱对代谢神经调节的影响

基本信息

批准号：
7651529
负责人：
Joseph Bass
金额：
$ 27.77万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-15 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7651529
关键词：
Adipose tissue Adult Age Age-Months Aging Alleles Animals Back Bass Behavior Behavioral Biochemical Markers Body Composition Brain Cell Count Cholesterol Circadian Rhythms Clinical Clock protein Complement Data Defect Dependence Desire for food Deterioration Development Diabetes Mellitus Diet Disease Doctor of Philosophy Doxycycline Elderly Electroencephalography Energy Metabolism Engineering Fatty Acids Fatty Liver Fatty acid glycerol esters Feeding behaviors Food Gene Expression Gene Mutation Genes Genetic Genetic Models Genetic Transcription Glucagon Glucocorticoids Glucose Goals Histology Homeostasis Hormonal Human Hyperglycemia Hyperlipidemia Hypertriglyceridemia Hypertrophy Hypothalamic structure Impairment Instruction Insulin Insulin Resistance Investigation Knowledge Laboratories Lead Length Leptin Life Light Link Lipids Liver Liver Glycogen Living Wills Measures Medial Mediating Metabolic Metabolic Diseases Metabolic Marker Metabolic Pathway Metabolic syndrome Metabolism Methods Modeling Molecular Monitor Motion Motor Activity Mus Muscle Mutant Strains Mice Mutation Neuropeptide Gene Neuropeptides Obesity Pancreas Pathology Pathway interactions Peripheral Phase Phenotype Physiology Polysomnography Predisposition Prevention Principal Investigator Process Puberty REM Sleep Recovery Relative (related person)Reporting Research Personnel Rest Risk Risk Factors Rodent Role Satiation Science Severities Sleep Sleep disturbances Switch Genes Syndrome System Testing Tetracyclines Time Tissues Triglycerides Visceral Wakefulness Wild Type Mouse Work adiponectin age related base circadian pacemaker drinking water emerging adult feeding food consumption gene function glucose tolerance improved insight insulin tolerance mutant neurobehavioral neuroregulation obesity risk prevent programs research study sleep regulation stem tool

项目摘要

Seeinstructions): The long-term goal of this project is to dissect the molecular basis for accelerated metabolic aging induced by circadian disruption and sleep loss in mice. Consistent with the overall goals of this program project, our focus will be to exploit mouse genetic tools to uncover the effect of circadian disruption at distinct time points in life on the progression of sleep impairment, and metabolic phenotypes. Our focus stems from work that has established that (1) circadian Clock mutant mice develop sleep loss and severe cardiometabolic disease during aging and (2) that high-fat diet itself leads to altered behavioral and molecular circadian rhythms in mice. We hypothesize that a 'vicious cycle' interconnects sleep and circadian disruption with cardiometabolic diisease. Moreover, we propose that there circadian disruption during critical windows in life effect the severity of cardiometabolic disease. We propose to exploit a genetic rescue strategy in which we have engineered clock mice harboring tetracycline-inducible wild-type alleles of the clock gene that can be selectively turned on or off within brain at distinct time points throughout life. Clock brain rescue mice have normal locomotor activity rhythms, but we do not know whether they also have normalized sleep and/or normalized metabolic profiles. Here we propose to test they hypothesis that clock gene rescue in brain at distinct ages either in early life or adulthood has different effects on sleep and the progression of cardiometabolic disease. In Aim 1, we propose to rescue clock function in brain throughout life; in Aim 2 we propose to rescue only in early life; and in Aim 3 we propose to rescue clock function in brain in adult life. We will then analyze sleep (REM/NREM/delta power) and metabolic endpoints (feeding rhythms, body composition, hormonal/biochemical markers and tissue metabolic gene networks). Results of these studies will establish the cause-and-effect relationship between disruption of circadian systems, sleep, and metabolic homeostasis and pinpoint the most vulnerable periods in life that set in motion an irreversible course of accelerated aging. RELEVANCE (See instructions): The goal of this proposal is to dissect the molecular basis for accelerated metabolic aging induced by circadian disruption and sleep loss in mice. Insight gained from these studies will advance our knowledge of the interdependence of circadian disruption, sleep impairment, and cardiometabolic disease. We will establish the age-dependence of altered behavior on metabolic aging and create new insight for both prevention and rational theranies that will avert diabetes and ohfisitv durinn aninn.

参见说明）：该项目的长期目标是剖析加速代谢衰老引起的分子基础小鼠的昼夜节律紊乱和睡眠不足。与该计划项目的总体目标一致，我们重点是利用小鼠遗传工具来揭示昼夜节律紊乱在不同时间点的影响生活中睡眠障碍的进展和代谢表型。我们的重点源于工作已确定 (1) 昼夜节律时钟突变小鼠会出现睡眠不足和严重的心脏代谢疾病在衰老过程中，（2）高脂肪饮食本身会导致行为和分子昼夜节律的改变老鼠。我们假设“恶性循环”将睡眠和昼夜节律紊乱与心脏代谢疾病。此外，我们建议在生命的关键窗口期间存在昼夜节律紊乱影响心脏代谢疾病的严重程度。我们建议开发一种基因拯救策略，其中我们已经设计出带有四环素诱导的野生型时钟基因等位基因的时钟小鼠，该等位基因可以在一生中的不同时间点，大脑有选择性地开启或关闭。时钟脑救援小鼠有正常的运动活动节律，但我们不知道他们是否也有正常的睡眠和/或标准化代谢曲线。在这里，我们建议测试他们的假设，即大脑中的时钟基因拯救生命早期或成年时期的不同年龄对睡眠和睡眠的进展有不同的影响心脏代谢疾病。在目标 1 中，我们建议在一生中挽救大脑的时钟功能；在目标 2 中，我们建议仅在生命早期进行救助；在目标 3 中，我们建议挽救成人生活中大脑的时钟功能。然后，我们将分析睡眠（REM/NREM/delta 功率）和代谢终点（进食节律、身体成分、激素/生化标记物和组织代谢基因网络）。这些研究的结果将建立昼夜节律系统破坏、睡眠和代谢之间的因果关系体内平衡并查明生命中最脆弱的时期，这些时期启动了不可逆转的进程加速老化。相关性（参见说明）：该提案的目标是剖析加速代谢衰老的分子基础小鼠的昼夜节律紊乱和睡眠不足。从这些研究中获得的见解将增进我们的知识昼夜节律紊乱、睡眠障碍和心脏代谢疾病之间的相互依赖性。我们将确定行为改变对代谢衰老的年龄依赖性，并为两者创造新的见解预防和合理治疗可避免糖尿病和糖尿病。