Consequences of Circadian Desynchrony

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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.