Consequences of Circadian Desynchrony

描述（由申请人提供）：轮班工作与许多不良健康结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新设置为环境的持续“应激”、将外周组织中的时钟重新设置为下丘脑时钟的持续“应激”或两者所致。我们最近开发了具有两个酪蛋白激酶1（CK1）基因（CK1 δ和CK1 β）的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在昼夜节律周期长度（周期）上有适度的改变，但是CK1 δ的两个等位基因和CK1 δ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等位基因的脑特异性破坏导致小鼠的脑时钟每天运行约27小时，并且外周正常（周期长度接近24小时）。我们已经组建了一个具有不同专业知识的团队，以调查这些突变小鼠的昼夜节律的代价。我们的总体假设是，昼夜节律紊乱将导致对健康的不利后果。我们提出的研究的总体目标是评估由大脑遗传操纵产生的昼夜节律紊乱是否会导致不良的健康后果。我们将首先评估外周组织和大脑的节律，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影响。基于先前的文献，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。我们的研究将是第一个评估生物钟之间同步的重要性，而不会反复将大脑时钟重置为破坏性的照明周期。我们预计，即使SCN时钟没有反复重置，整个身体的生物钟之间失去同步也会产生不良后果。这一发现将有重要的影响，药理学和非侵入性（光，行为，褪黑激素）的战略，旨在对抗倒班工作的不利影响，以及揭示哺乳动物昼夜节律计时系统的分层性质的重要特征。

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.