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Consequences of Circadian Desynchrony

昼夜节律不同步的后果

基本信息

批准号：
8878263
负责人：
DAVID Raymond WEAVER
金额：
$ 20.98万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8878263
关键词：
Address Alleles Animals Back Behavioral Biological Clocks Biology Bioluminescence Body Composition Brain Cardiovascular Diseases Casein Kinase Iepsilon Cells Chronic Circadian Rhythms Data Development Diet Disease Environment Fatty acid glycerol esters Gastrointestinal Diseases Gene Expression Genes Genotype Glucose Health Heart Hour Hypothalamic structure Incidence Individual Intervention Jet Lag Syndrome Kidney Lead Length Light Lighting Literature Malignant Neoplasms Mammals Melatonin Mental Depression Metabolic Metabolism Modeling Morbidity - disease rate Mus Mutant Strains Mice Nature Obesity Organism Outcome Pathology Periodicity Peripheral Phase Physiological Population Predisposition Process Relative (related person)Running Stress System Testing Time Tissues adverse outcome age related base brain tissue casein kinase I circadian pacemaker cost genetic manipulation in vivo insulin sensitivity light effects mouse model public health relevance research study response shift work theories

项目摘要

DESCRIPTION (provided by applicant): Shift work is associated with an increased incidence of numerous adverse health outcomes. These pathological responses are thought to result from the continual "stress" of re-setting the hypothalamic circadian pacemaker to the environment, the continual "stress" of re-setting clocks in peripheral tissues to the hypothalamic clock, or both. We recently developed mouse lines with conditional alleles of two casein kinase 1 (CK1) genes, CK1 delta and CK1 epsilon. These genes can be disrupted in a tissue-specific manner. Mice and tissues with disruption of most combinations of these conditional alleles have modest alterations in circadian cycle length (period), but mice, cells and tissues with disruption of both alleles of CK1delta and one allele of CK1 epsilon have a ~ 3-hour lengthening of circadian period. Notably, brain-specific disruption of these three CK1 alleles leads to mice with a brain clock running at ~27-hr per day, and a periphery that is normal (period length near 24 hr). We have assembled a team with diverse expertise to investigate the costs of circadian desynchrony in these mutant mice. Our overall hypothesis is that circadian desynchrony will lead to adverse consequences for health. The overall objective of our proposed studies is to assess whether circadian desynchrony, produced by genetic manipulation of the brain, leads to adverse health consequences. We will first assess rhythms in peripheral tissues and brain to assess their level of coordination in mice of different genotypes following tissue-specific gene disruption. We will then assess the pathophysiological impact of these altered temporal relationships. Based on prior literature, we will focus on metabolic responses (glucose handling and insulin sensitivity, body composition, susceptibility to diet-induced obesity), and histopathological changes in heart and kidney. Our studies will be the first to assess the importance of synchronization among circadian clocks without the potential confounding influence of repeatedly resetting the brain clock to a disruptive lighting cycle. We expect that loss of synchrony between circadian clocks throughout the body will have adverse consequences, even when the SCN clock is not faced with repeatedly re-setting. This finding would have important implications for pharmacological and non-invasive (light, behavioral, melatonin) strategies aimed at countering the adverse impact of shift work, as well as revealing important features of the hierarchical nature of the mammalian circadian timing system.

描述（由申请人提供）：轮班工作与多种不良健康后果的发生率增加有关。这些病理反应被认为是由于将下丘脑昼夜节律起搏器重置为环境的持续“压力”、将外周组织中的时钟重置为下丘脑时钟的持续“压力”，或两者兼而有之。我们最近开发了具有两个酪蛋白激酶 1 (CK1) 基因 CK1 delta 和 CK1 epsilon 条件等位基因的小鼠品系。这些基因可以以组织特异性方式被破坏。这些条件等位基因的大多数组合被破坏的小鼠和组织的昼夜节律周期长度（周期）有适度的改变，但是CK1delta的两个等位基因和CK1 epsilon的一个等位基因被破坏的小鼠、细胞和组织的昼夜节律周期延长约3小时。值得注意的是，这三个 CK1 等位基因的大脑特异性破坏导致小鼠的大脑时钟每天运行约 27 小时，而外周正常（周期长度接近 24 小时）。我们组建了一支具有不同专业知识的团队来研究这些突变小鼠昼夜节律不同步的成本。我们的总体假设是昼夜节律不同步会对健康造成不利后果。我们提出的研究的总体目标是评估由大脑基因操纵产生的昼夜节律不同步是否会导致不良的健康后果。我们将首先评估周围组织和大脑的节律，以评估组织特异性基因破坏后不同基因型小鼠的协调水平。然后我们将评估这些改变的时间关系的病理生理学影响。根据先前的文献，我们将重点关注代谢反应（葡萄糖处理和胰岛素敏感性、身体成分、饮食引起的肥胖的易感性）以及心脏和肾脏的组织病理学变化。我们的研究将首次评估生物钟之间同步的重要性，而不会因反复将大脑时钟重置为破坏性的照明周期而产生潜在的混淆影响。我们预计，即使 SCN 时钟没有面临反复重新设置，全身生物钟之间失去同步也会产生不利后果。这一发现将对药理学和非侵入性（光、行为、褪黑激素）策略产生重要影响，这些策略旨在对抗轮班工作的不利影响，并揭示哺乳动物昼夜节律计时系统的层次性质的重要特征。