Speaker
Description
Circadian (~ 24 h) rhythms can be synchronized to the earth’s 24 h periodic environment through external cues such as light - dark (LD) cycle. The misalignment of circadian timings with the external environment can lead to crucial physiological problems, such as jet lag, bipolar disorders and cancer. To treat the misalignment problem, we investigate the pharmacological manipulation of circadian phase of primates, Cynomolgus monkeys using the casein kinase1 δ/ε inhibitor, PF-670462. Surprisingly, we observed that the PF-670462-induced phase shift of primates (diurnal species) is less than that of mice (nocturnal species) under LD while that of primates is larger than that of mice under DD. To understand this unexpected phenomenon, we used mathematical modelling and found that the light sensitivity of primate’s circadian rhythm depending on circadian phase is different to that of mouse’s circadian rhythm. Furthermore, the PF-670462-induced phase shift is dramatically different depending on dosing amount and timing, light condition and chronotype. Thus, it is challenging to identify the dosing amount and timing to induce a desired phase shift. Here, we found a simple strategy to identify personalized dosing amounts and timing regardless of season and chronotype to treat advanced sleep phase disorder using mathematical modelling.
[1] Jae Kyoung Kim et. al., Modeling and Validating Chronic Pharmacological Manipulation of Circadian Rhythms, CPT: Pharmacometrics & Systems Pharmacology (2013)
[2] Jeffrey Sprouse et. al., Inhibition of casein kinase1ε/δ, produces phase shifts in the circadian rhythms of Cynomolgus monkeys, Psychopharmacology, pp. 735-742 (2009)
[3] Caroline H.Ko et. al., Molecular components of the mammalian circadian clock, Human Molecular Genetics, Vol. 15, pp. 271-277 (2013)
[4] Jae Kyoung Kim et. al., A mechanism for robust circadian timekeeping via stoichiometric balance, Molecular Systems Biology (2010)
[5] Florian Geier et. al., Entrainment in a Model of the Mammalian Circadian Oscillator, Journal of Biological Rhythms (2005)
