Computational approaches to cellular rhythms

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Computational approaches to cellular
rhythms

• Albert Goldbeter
• Unité de Chronobiologie théorique,
• Faculté des Sciences, Université Libre de
  Bruxelles

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Main biological rhythms
P53, NFKB, Msn2,
A. Goldbeter (1996) Biochemical Oscillations
and Cellular Rhythms, CUP.
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Why are there so many rhythms in
biological systems?
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Why are there so many rhythms in
biological systems?
Nonlinearities
Regulations
Instabilities
Oscillations
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Regulations and cellular rhythms
Regulation of
Ion channel Neural and cardiac
rhythms Enzyme Glycolytic oscillations in
yeast Receptor cAMP oscillations in
Dictyostelium Transport Ca2 oscillations,
Mns2 in yeast Gene expression Circadian
rhythms
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• Circadian rhythms

Circadian rhythms (T 24 h) are endogenous
sincethey persist under constant conditions,
e.g. continuousdarkness (DD) or light (LL)
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Periodic variation of PER protein and per mRNA
Zeng, Hardin Rosbash (1994) EMBO J. 13, 3590-8.
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Core mechanism of circadian rhythms
Cf. Goodwin, 1965
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Core model for the Drosophila circadian clock
A. Goldbeter (1995). Proc. R. Soc. Lond. B 261,
319-324.
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Goldbeter (1995). Proc. R. Soc. Lond. B
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Role of TIM in the control of circadian
rhythms by light in Drosophila
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A model for circadian rhythms in Drosophila
incorporating the formation of a complex between
the PER and TIM proteins J. C. Leloup A.
Goldbeter (1998) J. Biol. Rhythms 1370-87.
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Circadian oscillations in DD, LD and LL
Leloup and Goldbeter (1998) J. Biol. Rhythms
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Phase shift by a light pulse
Phase response curve
Leloup and Goldbeter (2000) BioEssays
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Suppression of circadian rhythms by a single
pulse of light
Coexistence of a stablesteady state and a
stable rhythm
Leloup and Goldbeter (2001) Am. J. Physiol..
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Stochastic vs deterministic models for circadian
rhythms
Gonze et al, PNAS (2002), J. Biol. Phys. (2004)
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Science (1999) 286, 766-8   Interlocked
feedback loops within the Drosophila circadian
oscillator.Glossop NR, Lyons LC, Hardin PE.
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Model for the mammalian circadian clock
J.C. Leloup A. Goldbeter (2003) PNAS 100,
7051-56.
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Leloup and Goldbeter (2003) PNAS
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Multiple sources of oscillations
Leloup and Goldbeter PNAS (2003), JTB (2004)
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Link with disorders of the sleep-wake cycle
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Link with disorders of the sleep-wake cycle
Science 291, 1040-1043 (2001)
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Leloup and Goldbeter (2003) PNAS
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Sometimes entrainment fails to occur
One possible cause CRY levels are too low
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Non 24 h sleep-wake syndrome
Phase jump
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Models can be used to study the molecular
basesof biological rhythms as well as the
physiologicaldisorders related to dysfunctions
of these rhythms. Computational models suggest
systems-based approaches to treat such
physiological disorders.