C39D6A46d01 - Modeling the molecular mechanism of circadian...

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Modeling the molecular mechanism of circadian clocks Didier Gonze (1) Laboratoire de Bioinformatique des Génomes & des Réseaux (2) Unité de Chronobiologie théorique Université Libre de Bruxelles Belgium
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Ideker T & Lauffenburger D. (2003) Trends in Biotechnology 21: 252-262. High- vs low-level of modeling
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High- vs low-level of modeling Unit é de Chronobiologie Théorique (Prof. A. Goldbeter) Laboratoire de Bioinformatique des Génomes et des Réseaux (Prof. J. van Helden) http://www.bigre.ulb.ac.be/ http://www.ulb.ac.be/sciences/utc/
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Biological rhythms RHYTHM PERIOD Neuronal rhythms * Cardiac rhythms * Calcium oscillations * Biochemical oscillations * Mitotic cycle * Hormonal rhythms * Circadian rhythms * Ovarian cycle Annual rhythms Epidemiological and ecological oscillations 0.01 to 10 s (and more?) 1 s 1 s to several minutes 1 to 20 min 10 min to 24 h (or more) 10 min to several hours (also 24 h) 24 h 28 days (for humans) 1 year Years Some recently discovered rhythms Min oscillation in E. Coli 40 s (Hu & Lutkenhaus, Mol Microbiol 1999) Msn2 shuttling 6 min (Jacquet et al., J Cell Biol 2003) Yeast transcriptome 40 min (Klevecz & Murray, Mol Biol Rep 2001) Segmentation clock 90 min (Palmeirim et al., Cell 1997) Socs3/Smad6 2 h (Yoshiura et al., PNAS 2007) p53 3 h (Bar-Or et al. , PNAS 2000) NFkB 6 h (Hoffmann et al., Science 2002) Goldbeter A (1996) Biochemical Oscillations and Cellular Rhythms: The molecular bases of periodic and chaotic behaviour. Cambridge University Press, Cambridge, UK .
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Circadian rhythms Circadian rhythms are endogeneous biological rhythms characterized by a period of about 24h ... Jean-Jacques d’Ortous de Mairan (1740) La sensitive sent donc le soleil sans le voir en aucune manière
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Circadian rhythms Circadian rhythms are ubiquitous . They allow living organisms to live in phase with the alternance of day and night. ..
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Circadian rhythms Many physiological functions are regulated by the circadian clock: blood pressure, hormone secretion, sleep, heart beat,. .. Figure from: http://en.wikipedia.org/wiki/Circadian_rhythm
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Circadian rhythms In constant conditions, the free- running period of circadian rhythm is around 24h (but not exactly 24h) In natural conditions circadian rhythms are entrained by the external light-dark cycle and the period is exactly 24h. Franz Halberg (born in 1919) Father of Chronobiology Coined the term circadian (1959) Free-run vs entrainment circa (around) dies (day)
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Circadian rhythms: genetic bases Locomotor activity Konopka RJ & Benzer S (1971) Clock mutants of Drosophila melanogaster . Proc Natl Acad Sci USA 68, 2112-6. Identification of the period ( per ) gene X chromosome Drosophila
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Circadian rhythms: genetic bases Expression of the per gene Zeng H, Hardin PE, Rosbash M (1994) Constitutive overexpression of the Drosophila period protein inhibits period mRNA cycling. EMBO J. 13: 3590-3598.
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Molecular mechanism of circadian clocks clock gene Drosophila per (period), tim (timeless) Mammals mper1-3 (period homologs) Neurospora frq (frequency) Core mechanism: negative feedback loop
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