Systems approach reveals photosensitivity and PER 2 level as determinants of clock‐modulator efficacy

Abstract

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 CK 1δ/ε 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 CK 1δ/ε 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 CK 1δ/ε inhibition strongly depends on endogenous PER 2 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.

Multiple random phosphorylations in clock proteins provide long delays and switches

“…In both cases intrinsically disordered proteins (FRQ and PER, respectively) with multiple random phosphorylations are central players within the negative transcriptional-translational feedback loop 21,72,84,85 . Interestingly, the control of the delay via phosphorylations is also a target of pharmacological interventions 86,87 . Below we focus on the Neurospora clock.…”

“…A7 we show that step by step decreasing and increasing phosphorylation rates and varying stability do not change our main results. Such simulations are a first step towards more detailed incorporation of the effects of specific phosphorylations 86 . In future studies, stabilizing effects of FRH 55 , interactions with WCC 23 , and degradation assisted by FWD1 78 could be incorporated.…”

Novel Comprehensive Bioinformatics Approaches to Determine the Molecular Genetic Susceptibility Profile of Moderate and Severe Asthma

“…PER2 had a high significance in the moderate-to-severe asthma dataset (Figure 1 and Table S1). This is not surprising, given that polymorphisms in this gene could increase the risk of developing certain cancers and have been associated with sleep disorders [50].The association between asthma and sleep disorders could explain the high level of circadian CLOCK-related gene expression (PER2 and GCR) and the high interaction activity of the TIMELESS gene in PPIs for the moderate-to-severe asthma phenotype ( Figure 4C). Such an association has been discussed in some studies on gene expression [51], indicating the consequences of such mechanical surveillance disorder and the severity of asthma.…”

A dual-feedback loop model of the mammalian circadian clock for multi-input control of circadian phase

“…Similarly, the simulation did not account for other naturally occurring environmental inputs to the circadian clock, including light and metabolic cues. Light has been shown to be a valuable control input to shift phase, and as a result, the light environment may change the efficacy of these small molecules [ 40 ].…”