Modeling and validating chronic pharmacological manipulation of circadian rhythms

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Circadian rhythms can be entrained by a light-dark (LD) cycle and can also be reset pharmacologically, for example, by the CK1?/? inhibitor PF-670462. Here, we determine how these two independent signals affect circadian timekeeping from the molecular to the behavioral level. By developing a systems pharmacology model, we predict and experimentally validate that chronic CK1?/? inhibition during the earlier hours of a LD cycle can produce a constant stable delay of rhythm. However, chronic dosing later during the day, or in the presence of longer light intervals, is not predicted to yield an entrained rhythm. We also propose a simple method based on phase response curves (PRCs) that predicts the effects of a LD cycle and chronic dosing of a circadian drug. This work indicates that dosing timing and environmental signals must be carefully considered for accurate pharmacological manipulation of circadian phase. © 2013 ASCPT.
Publisher
Nature Publishing Group
Issue Date
2013-07
Language
English
Citation

CPT: Pharmacometrics and Systems Pharmacology, v.2, no.7, pp.0 - 0

ISSN
2163-8306
DOI
10.1038/psp.2013.34
URI
http://hdl.handle.net/10203/203041
Appears in Collection
MA-Journal Papers(저널논문)
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