Mathematical Modelling of Peripheral Metabolic Circadian Rhythms: Implications for Shift Work and Jetlag Management - Project Summary/Abstract Millions of adults experience circadian rhythm disruption daily due to shift work, transmeridian travel or irregular sleep schedules, leading to short-term symptoms of jetlag as well as longer-term adverse health outcomes. While effective interventions to treat circadian disruption using for example light exposure or exogenous melatonin are available, these typically aim to resynchronize only centrally controlled circadian rhythms. In contrast, circadian disruption of peripherally controlled rhythms and interventions to resynchronize peripheral circadian rhythms are underdeveloped. The disruption of peripheral circadian rhythms may underlie the short- term gastrointestinal symptoms many people experience with transmeridian travel or rotating between day and night shifts, and chronic disruption of these peripheral circadian rhythms may be a significant risk factor for developing cardiometabolic disease. Mathematical models of the human circadian system have played an important role in developing sleep- and circadian-informed lighting interventions for mitigating symptoms of central circadian rhythm disruption, but until recently there has not been sufficient evidence to develop and validate models for peripheral circadian rhythms. Emerging evidence from our group and others indicates that while light remains the primary synchronizer of central circadian rhythms, meal timing may be the primary synchronizer for peripheral circadian rhythms including those of circulating serum lipids in humans. For example, we have identified robust circadian rhythmicity in circulating serum cholesterol and preliminary findings from our current NHLBI-supported study indicates that cholesterol phase resets in response to changes in meal timing, even in the presence of circadian photobiologically inert dim light exposure. Given the utility of existing mathematical models to design sleep- and circadian-informed lighting interventions for central circadian rhythms, we propose in this project to take a data-driven approach that leverages our current mathematical framework— the Kronauer-Jewett-St Hilaire (KJS) model of the effects of photic and non-photic stimuli on the human circadian system—to develop and validate a novel mathematical model of the effect of meal timing on peripheral circadian rhythms. We will use the existing mathematical framework and systematic modeling approaches to incorporate cholesterol phase as a peripheral circadian rhythm, add meal timing as an additional non-photic stimulus in the model, and use data from multiple studies collected under highly controlled laboratory conditions to refine and validate the model against experimental cholesterol phase response curves to meal timing. We expect the mathematical model of the peripheral circadian system that results from this work will be used in tandem with the existing mathematical model of the central circadian system as foundational tools for developing and testing multifaceted interventions for comprehensively treating both peripheral and central circadian disruption that occurs during shift work, transmeridian travel, and irregular sleep schedules.
