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The circadian clock orchestrates temporal patterns of physiology and behavior relative to the environmental light:dark cycle by generating and organizing transcriptional and biochemical rhythms in cells and tissues throughout the body. Circadian clock genes have been shown to regulate the physiology and function of the gastrointestinal tract. Disruption of the intestinal epithelial barrier enables the translocation of proinflammatory bacterial products, such as endotoxin, across the intestinal wall and into systemic circulation; a process that has been linked to pathologic inflammatory states associated with metabolic, hepatic, cardiovascular and neurodegenerative diseases - many of which are commonly reported in shift workers. Here we report, for the first time, that circadian disorganization, using independent genetic and environmental strategies, increases permeability of the intestinal epithelial barrier (i.e., gut leakiness) in mice. Utilizing chronic alcohol consumption as a well-established model of induced intestinal hyperpermeability, we also found that both genetic and environmental circadian disruption promote alcohol-induced gut leakiness, endotoxemia and steatohepatitis, possibly through a mechanism involving the tight junction protein occludin. Circadian organization thus appears critical for the maintenance of intestinal barrier integrity, especially in the context of injurious agents, such as alcohol. Circadian disruption may therefore represent a previously unrecognized risk factor underlying the susceptibility to or development of alcoholic liver disease, as well as other conditions associated with intestinal hyperpermeability and an endotoxin-triggered inflammatory state.

The circadian clock has been linked to reproduction at many levels in mammals. Epidemiological studies of female shift workers have reported increased rates of reproductive abnormalities and adverse pregnancy outcomes, although whether the cause is circadian disruption or another factor associated with shift work is unknown. Here we test whether environmental disruption of circadian rhythms, using repeated shifts of the light:dark (LD) cycle, adversely affects reproductive success in mice. Young adult female C57BL/6J (B6) mice were paired with B6 males until copulation was verified by visual identification of vaginal plug formation. Females were then randomly assigned to one of three groups: control, phase-delay or phase-advance. Controls remained on a constant 12-hr light:12-hr dark cycle, whereas phase-delayed and phase-advanced mice were subjected to 6-hr delays or advances in the LD cycle every 5-6 days, respectively. The number of copulations resulting in term pregnancies was determined. Control females had a full-term pregnancy success rate of 90% (11/12), which fell to 50% (9/18; p<0.1) in the phase-delay group and 22% (4/18; p<0.01) in the phase-advance group. Repeated shifting of the LD cycle, which disrupts endogenous circadian timekeeping, dramatically reduces pregnancy success in mice. Advances of the LD cycle have a greater negative impact on pregnancy outcomes and, in non-pregnant female mice, require longer for circadian re-entrainment, suggesting that the magnitude or duration of circadian misalignment may be related to the severity of the adverse impact on pregnancy. These results explicitly link disruptions of circadian entrainment to adverse pregnancy outcomes in mammals, which may have important implications for the reproductive health of female shift workers, women with circadian rhythm sleep disorders and/or women with disturbed circadian rhythms for other reasons.

Disruption of circadian rhythms results in metabolic dysfunction. Casein kinase 1 epsilon (CK1ε) is a canonical circadian clock gene. Null and tau mutations in CK1ε show distinct effects on circadian period. To investigate the role of CK1ε in body weight regulation under both regular chow (RC) and high fat (HF) diet conditions, we examined body weight on both RC and HF diets in CK1ε-/- and CK1εtau/tau mice on a standard 24 hr light-dark (LD) cycle. Given the abnormal entrainment of CK1εtau/tau mice on a 24 hr LD cycle, a separate set of CK1εtau/tau mice were tested under both diet conditions on a 20 hr LD cycle, which more closely matches their endogenous period length. On the RC diet, both CK1ε-/- and CK1εtau/tau mutants on a 24 hr LD cycle and CK1εtau/tau mice on a 20 hr LD cycle exhibited significantly lower body weights, despite similar overall food intake and activity levels. On the HF diet, CK1εtau/tau mice on a 20 hr LD cycle were protected against the development of HF diet-induced excess weight gain. These results provide additional evidence supporting a link between circadian rhythms and energy regulation at the genetic level, particularly highlighting CK1ε involved in the integration of circadian biology and metabolic physiology.

A variety of environmental factors contribute to progressive development of osteoarthritis (OA). Environmental factors that upset circadian rhythms have been linked to various diseases. Our recent work establishes chronic environmental circadian disruption - analogous to rotating shiftwork-associated disruption of circadian rhythms in humans - as a novel risk factor for the development of OA. Evidence suggests shift workers are prone to obesity and also show altered eating habits (i.e., increased preference for high-fat containing food). In the present study, we investigated the impact of chronic circadian rhythm disruption in combination with a high-fat diet (HFD) on progression of OA in a mouse model. Our study demonstrates that when mice with chronically circadian rhythms were fed a HFD, there was a significant proteoglycan (PG) loss and fibrillation in knee joint as well as increased activation of the expression of the catabolic mediators involved in cartilage homeostasis. Our results, for the first time, provide the evidence that environmental disruption of circadian rhythms plus HFD potentiate OA-like pathological changes in the mouse joints. Thus, our findings may open new perspectives on the interactions of chronic circadian rhythms disruption with diet in the development of OA and may have potential clinical implications.

Inflammatory bowel disease (IBD) is driven by a breakdown in immune regulation and epithelial barrier function, yet the contribution of eosinophils to this process has remained poorly defined and controversial. While eosinophils infiltrate the intestinal mucosa during both flares and remission, their role in shaping disease outcomes is unclear. Our RNA-seq analyses of colonic eosinophils isolated from dextran sulfate sodium (DSS)-treated mice revealed a significant upregulation of cyclooxygenase (Cox)-2 (gene name, ). Eosinophil-specific deletion of Cox-2 (Ptgs2 eoCre ) reduced IL-22 production and exacerbated DSS- and trinitrobenzene sulfonic acid (TNBS)-induced colitis, characterized by greater weight loss, higher disease activity, colon shortening, and epithelial injury. Administration of recombinant IL-22 reversed these phenotypes. Mechanistically, eosinophil-derived COX-2 enhanced IL-22 production by type 3 Innate lymphoid cells (ILC3s) through prostaglandin E2 (PGE ) signaling. Consistently, Ptgs2 eoCre mice exhibited reduced colonic PGE levels, while PGE analog treatment restored IL-22 production and mucosal protection. Our findings identify eosinophil-derived COX-2 and PGE as a critical regulator of IL-22 production during colitis, uncovering a previously unrecognized eosinophil-ILC3 crosstalk that safeguards the intestinal barrier and represents a promising therapeutic target in IBD.

Disruption of circadian rhythms results in metabolic dysfunction. Casein kinase 1 epsilon (CK1[epsilon]) is a canonical circadian clock gene. Null and tau mutations in CK1[epsilon] show distinct effects on circadian period. To investigate the role of CK1[epsilon] in body weight regulation under both regular chow (RC) and high fat (HF) diet conditions, we examined body weight on both RC and HF diets in [CK1[epsilon].sup.-/-] and [CK1[epsilon].sup.tau/tau] mice on a standard 24 hr light-dark (LD) cycle. Given the abnormal entrainment of [CK1[epsilon].sup.tau/tau] mice on a 24 hr LD cycle, a separate set of [CK1[epsilon].sup.tau/tau] mice were tested under both diet conditions on a 20 hr LD cycle, which more closely matches their endogenous period length. On the RC diet, both CK1[epsilon]~h and [CK1[epsilon].sup.tau/tau] mutants on a 24 hr LD cycle and [CK1[epsilon].sup.tau/tau] mice on a 20 hr LD cycle exhibited significantly lower body weights, despite similar overall food intake and activity levels. On the HF diet, [CK1[epsilon].sup.tau/tau] mice on a 20 hr LD cycle were protected against the development of HF diet-induced excess weight gain. These results provide additional evidence supporting a link between circadian rhythms and energy regulation at the genetic level, particularly highlighting CK1[epsilon] involved in the integration of circadian biology and metabolic physiology.

Motivation: Cellular, physiological and molecular processes must be organized and regulated across multiple time domains throughout the lifespan of an organism. The technological revolution in molecular biology has led to the identification of numerous genes implicated in the regulation of diverse temporal biological processes. However, it is natural to question whether there is an underlying regulatory network governing multiple timescales simultaneously. Results: Using queries of relevant databases and literature searches, a single dense multiscale temporal regulatory network was identified involving core sets of genes that regulate circadian, cell cycle, and aging processes. The network was highly enriched for genes involved in signal transduction (P = 1.82e-82), with p53 and its regulators such as p300 and CREB binding protein forming key hubs, but also for genes involved in metabolism (P = 6.07e-127) and cellular response to stress (P = 1.56e-93). These results suggest an intertwined molecular signaling network that affects biological time across multiple temporal scales in response to environmental stimuli and available resources.

Circadian rhythms are fundamental, nearly ubiquitous biological processes that enable organisms to anticipate and prepare for predictable environmental changes that arise due to the rotation of the Earth about its axis every 24 hours. They are controlled by a cell-autonomous, genetically-encoded molecular pacemaker that is found in nearly all cells and tissues of the body. This clock regulates and integrates multiple biochemical, molecular and physiological pathways, as well as various behaviors, thus orchestrating a temporal program that optimizes biological function in context of the day-night cycle. Epidemiological, clinical and experimental evidence all consistently implicate disturbed circadian rhythms as a contributing factor for physiological dysfunction and increased disease risk. The rapid and vast growth in understanding of how circadian rhythms are intertwined with biological pathways provides a foundation upon which time on a 24-hour basis can be incorporated into medicine, providing new opportunities for improving diagnostics, therapeutics and patient care. Within this framework, this dissertation will describe original research using mouse models demonstrating specific adverse physiological consequences that arise from circadian disruption. First, an experiment examining the impact of exposure to phase-shifts of the light:dark cycle, a model of shift work, on reproductive success will be described. Next, a series of experiments exploring the effects of circadian disruption on the integrity of the intestinal epithelial barrier and pathological responses to chronic alcohol consumption will be discussed. The impact of circadian disruption and alcohol on the composition and structure of the intestinal microbiota will then be discussed, followed by a description of the induced alterations in gene expression profiles in hippocampal, intestine and liver tissues. Finally, the observation that the timing of daily presentation of a freshly prepared liquid diet led to significant changes in feeding rhythms and the amount of food intake will be described. These findings will be considered in the context of the scientific literature and the gaps in knowledge that are addressed by this research. In summary, these findings underscore the importance of circadian disruption as a risk factor contributing to the development and progression of physiological aberrations, highlighting its relevance for the maintenance of health and prevention of disease.

Disrupted sleep has a profound adverse impact on lives of Parkinson's Disease (PD) patients and their caregivers. Sleep disturbances are exceedingly common in PD, with substantial heterogeneity in type, timing, and severity. Among the most common sleep-related symptoms reported by PD patients are insomnia, excessive daytime sleepiness, and sleep fragmentation, characterized by interruptions and decreased continuity of sleep. Alterations in brain wave activity, as measured on the electroencephalogram (EEG), also occur in PD, with changes in the pattern and relative contributions of different frequency bands of the EEG spectrum to overall EEG activity in different vigilance states consistently observed. The mechanisms underlying these PD-associated sleep-wake abnormalities are poorly understood, and they are ineffectively treated by conventional PD therapies. To help fill this gap in knowledge, a new progressive model of PD - the MCI-Park mouse- was studied. Near the transition to the parkinsonian state, these mice exhibited significantly altered sleep-wake regulation, including increased wakefulness, decreased non-rapid eye movement (NREM) sleep, increased sleep fragmentation, reduced rapid eye movement (REM) sleep, and altered EEG activity patterns. These sleep-wake abnormalities mirror those identified in PD patients. Thus, this model may help elucidate the circuit mechanisms underlying sleep disruption in PD and identify targets for novel therapeutic approaches.Competing Interest StatementThe authors have declared no competing interest.Footnotes* https://doi.org/10.5281/zenodo.10079840* https://doi.org/10.5281/zenodo.10046587* https://doi.org/10.5281/zenodo.10055607