Consequences of Circadian Desynchrony

描述(由申请人提供)：倒班工作与许多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对环境重新设置下丘脑昼夜节律起搏器的持续“压力”，或者是将外围组织中的时钟重新设置为下丘脑时钟的持续“压力”，或者两者兼而有之。我们最近建立了两个酪蛋白激酶1(CK1)基因条件等位基因的小鼠系，CK1 Delta和CK1 epsilon。这些基因可以以特定于组织的方式被破坏。这些条件等位基因的大多数组合中断的小鼠和组织的昼夜周期长度(周期)变化不大，但CK1 Delta和CK1 epsilon的一个等位基因同时中断的小鼠、细胞和组织的昼夜周期延长约3小时。值得注意的是，这三个CK1等位基因的大脑特异性干扰导致小鼠的大脑时钟每天运行约27小时，而外围设备正常(周期长度近24小时)。我们已经组建了一个拥有不同专业知识的团队来调查这些突变小鼠的昼夜节律去同步化的成本。我们的总体假设是，昼夜节律不同步将导致对健康的不利后果。我们提议的研究的总体目标是评估由大脑的基因操作产生的昼夜节律去同步化是否会导致不利的健康后果。我们将首先评估外周组织和大脑中的节律，以评估不同基因类型的小鼠在组织特异性基因中断后的协调水平。然后我们将评估这些改变的时间关系的病理生理学影响。根据以前的文献，我们将集中于代谢反应(葡萄糖处理和胰岛素敏感性，身体成分，对饮食诱导的肥胖的易感性)，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，而不会因为反复将大脑时钟重新设置为破坏性的照明周期而产生潜在的混杂影响。我们预计，全身生物钟之间失去同步性将产生不良后果，即使SCN钟没有面临反复重新设置。这一发现将对旨在对抗轮班工作的不利影响的药理学和非侵入性(光、行为、褪黑素)策略具有重要意义，并揭示哺乳动物昼夜节律系统等级性质的重要特征。

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.