Your browser doesn't support javascript.
loading
Systems approach reveals photosensitivity and PER2 level as determinants of clock-modulator efficacy.
Kim, Dae Wook; Chang, Cheng; Chen, Xian; Doran, Angela C; Gaudreault, Francois; Wager, Travis; DeMarco, George J; Kim, Jae Kyoung.
Afiliación
  • Kim DW; Department of Mathematical Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
  • Chang C; Clinical Pharmacology, Pfizer Global Product Development, Pfizer Inc., Groton, CT, USA.
  • Chen X; Comparative Medicine, Worldwide Research & Development, Pfizer Inc., Cambridge, MA, USA.
  • Doran AC; Enzymology and Transporter Group, Pharmacokinetics, Dynamics and Metabolism, Worldwide Research & Development, Pfizer Inc., Groton, CT, USA.
  • Gaudreault F; Clinical Pharmacology and Pharmacometrics, Research & Development, Biogen Inc., Cambridge, MA, USA.
  • Wager T; Neuroscience Research Unit, Worldwide Research & Development, Pfizer Inc., Boston, MA, USA.
  • DeMarco GJ; Department of Animal Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
  • Kim JK; Department of Mathematical Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
Mol Syst Biol ; 15(7): e8838, 2019 07.
Article en En | MEDLINE | ID: mdl-31353796
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 CK1δ/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 CK1δ/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 CK1δ/ε 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.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ritmo Circadiano / Quinasa Idelta de la Caseína / Fototransducción / Proteínas Circadianas Period / Relojes Circadianos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Mol Syst Biol Asunto de la revista: BIOLOGIA MOLECULAR / BIOTECNOLOGIA Año: 2019 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ritmo Circadiano / Quinasa Idelta de la Caseína / Fototransducción / Proteínas Circadianas Period / Relojes Circadianos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Mol Syst Biol Asunto de la revista: BIOLOGIA MOLECULAR / BIOTECNOLOGIA Año: 2019 Tipo del documento: Article Pais de publicación: Reino Unido