Department of Animal Medicine
Biological Phenomena, Cell Phenomena, and Immunity | Molecular Biology | Neuroscience and Neurobiology | Pharmacology, Toxicology and Environmental Health | Systems Biology
In mammals, the master circadian clock synchronizes daily rhythms of physiology and behavior with the day-night cycle. Failure of synchrony, which increases the risk for numerous chronic diseases, can be treated by phase adjustment of the circadian clock pharmacologically, for example, with melatonin, or a CK1delta/epsilon inhibitor. Here, using in silico experiments with a systems pharmacology model describing molecular interactions, and pharmacokinetic and behavioral experiments in cynomolgus monkeys, we find that the circadian phase delay caused by CK1delta/epsilon inhibition is more strongly attenuated by light in diurnal monkeys and humans than in nocturnal mice, which are common preclinical models. Furthermore, the effect of CK1delta/epsilon inhibition strongly depends on endogenous PER2 protein levels, which differs depending on both the molecular cause of the circadian disruption and the patient's lighting environment. To circumvent such large interindividual variations, we developed an adaptive chronotherapeutics to identify precise dosing regimens that could restore normal circadian phase under different conditions. Our results reveal the importance of photosensitivity in the clinical efficacy of clock-modulating drugs, and enable precision medicine for circadian disruption.
CK1δ/ε inhibitor, circadian rhythms, personalized chronotherapy, systems pharmacology model
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Copyright © 2019 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
DOI of Published Version
Mol Syst Biol. 2019 Jul;15(7):e8838. doi: 10.15252/msb.20198838. Link to article on publisher's site
Molecular systems biology
Kim DW, Chang C, Chen X, Doran AC, Gaudreault F, Wager T, DeMarco GJ, Kim JK. (2019). Systems approach reveals photosensitivity and PER2 level as determinants of clock-modulator efficacy. Open Access Publications by UMass Chan Authors. https://doi.org/10.15252/msb.20198838. Retrieved from https://escholarship.umassmed.edu/oapubs/3926
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
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