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Modeling and validating chronic pharmacological manipulation of circadian rhythms
J K Kim1, D B Forger, M Marconi
1Department of Mathematics, University of Michigan, Ann Arbor, Michigan, USA.
Abstract:
Circadian rhythms can be entrained by a light-dark (LD) cycle and can also be reset pharmacologically, for example, by the CK1δ/ε 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 CK1δ/ε 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.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e57; doi:10.1038/psp.2013.34; published online 17 July 2013.
Insights
Pharmacological inhibition of CK1δ/ε can delay circadian rhythms when timed correctly with light-dark cycles. However, improper timing or light exposure can prevent rhythm entrainment, highlighting the importance of signal timing.
Area of Science:
- Chronobiology
- Pharmacology
- Systems Biology
Background:
- Circadian rhythms are biological processes synchronized by environmental cues like light-dark cycles.
- Pharmacological agents, such as CK1δ/ε inhibitors, can also reset these rhythms.
- Understanding the interplay between environmental and pharmacological signals is crucial for manipulating circadian timing.
Purpose of the Study:
- To investigate how light-dark cycles and CK1δ/ε inhibition interact to affect circadian timekeeping.
- To predict and validate the effects of chronic pharmacological intervention on circadian rhythms.
- To develop a predictive method for combining environmental and drug-induced circadian phase shifts.
Main Methods:
- Development of a systems pharmacology model to simulate circadian rhythm dynamics.
- Experimental validation of model predictions using PF-670462, a CK1δ/ε inhibitor.
- Application of phase response curves (PRCs) to predict combined effects of light and drug treatment.
Main Results:
- Chronic CK1δ/ε inhibition early in the light-dark cycle can stably delay circadian rhythms.
- Dosing later in the day or with prolonged light exposure may not result in rhythm entrainment.
- A PRC-based method was proposed to predict the combined effects of light cycles and circadian drugs.
Conclusions:
- Dosing time is critical for successful pharmacological manipulation of circadian phase.
- Environmental signals (light-dark cycles) significantly influence the efficacy of circadian drugs.
- Careful consideration of both timing and environmental context is necessary for accurate pharmacological control of circadian rhythms.
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