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MODEL0478895291 - Leloup2004_CircadianRhythms


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Reference Publication
Publication ID: 15363675
Leloup JC, Goldbeter A.
Modeling the mammalian circadian clock: sensitivity analysis and multiplicity of oscillatory mechanisms.
J. Theor. Biol. 2004 Oct; 230(4): 541-562
Unité de Chronobiologie théorique, Faculté des Sciences, Université Libre de Bruxelles, Campus Plaine, C.P. 231, B-1050 Brussels, Belgium.  [more]
Original Model: CellML logo
Submitter: Vijayalakshmi Chelliah
Submission Date: 23 Apr 2009 14:17:12 UTC
Last Modification Date: 14 Jan 2011 14:11:12 UTC
Creation Date: 23 Apr 2009 14:17:12 UTC
bqmodel:isDerivedFrom PubMed 12775757
bqbiol:isVersionOf Gene Ontology entrainment of circadian clock by photoperiod
bqbiol:hasTaxon Taxonomy Homo sapiens

This a model from the article:
Modeling the mammalian circadian clock: sensitivity analysis and multiplicity of oscillatory mechanisms.
Leloup JC, Goldbeter A. J Theor Biol. 2004 Oct 21;230(4):541-62. 15363675 ,
We extend the study of a computational model recently proposed for the mammalian circadian clock (Proc. Natl Acad. Sci. USA 100 (2003) 7051). The model, based on the intertwined positive and negative regulatory loops involving the Per, Cry, Bmal1, and Clock genes, can give rise to sustained circadian oscillations in conditions of continuous darkness. These limit cycle oscillations correspond to circadian rhythms autonomously generated by suprachiasmatic nuclei and by some peripheral tissues. By using different sets of parameter values producing circadian oscillations, we compare the effect of the various parameters and show that both the occurrence and the period of the oscillations are generally most sensitive to parameters related to synthesis or degradation of Bmal1 mRNA and BMAL1 protein. The mechanism of circadian oscillations relies on the formation of an inactive complex between PER and CRY and the activators CLOCK and BMAL1 that enhance Per and Cry expression. Bifurcation diagrams and computer simulations nevertheless indicate the possible existence of a second source of oscillatory behavior. Thus, sustained oscillations might arise from the sole negative autoregulation of Bmal1 expression. This second oscillatory mechanism may not be functional in physiological conditions, and its period need not necessarily be circadian. When incorporating the light-induced expression of the Per gene, the model accounts for entrainment of the oscillations by light-dark (LD) cycles. Long-term suppression of circadian oscillations by a single light pulse can occur in the model when a stable steady state coexists with a stable limit cycle. The phase of the oscillations upon entrainment in LD critically depends on the parameters that govern the level of CRY protein. Small changes in the parameters governing CRY levels can shift the peak in Per mRNA from the L to the D phase, or can prevent entrainment. The results are discussed in relation to physiological disorders of the sleep-wake cycle linked to perturbations of the human circadian clock, such as the familial advanced sleep phase syndrome or the non-24h sleep-wake syndrome.

This model was taken from the CellML repository and automatically converted to SBML.
The original model was: Leloup JC, Goldbeter A. (2004) - version02
The original CellML model was created by:
Lloyd, Catherine, May
The University of Auckland
The Bioengineering Institute

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