Kervizic2008_Cholesterol_SREBP

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Short description

Model of cholesterol regulation (with Boolean Formulae) (2008)

This model is described in
Dynamical modeling of the cholesterol regulatory pathway with Boolean networks ; Gwenael Kervizic and Laurent Corcos, BMC Systems Biology 2008, 2:99 doi: 10.1186/1752-0509-2-99
Abstract:
Background: Qualitative dynamics of small gene regulatory networks have been studied in quite some details both with synchronous and asynchronous analysis. However, both methods have their drawbacks: synchronous analysis leads to spurious attractors and asynchronous analysis lacks computational efficiency, which is a problem to simulate large networks. We addressed this question through the analysis of a major biosynthesis pathway. Indeed the cholesterol synthesis pathway plays a pivotal role in dislypidemia and, ultimately, in cancer through intermediates such as mevalonate, farnesyl pyrophosphate and geranyl geranyl pyrophosphate, but no dynamic model of this pathway has been proposed until now.
Results: We set up a computational framework to dynamically analyze large biological networks. This framework associates a classical and computationally efficient synchronous Boolean analysis with a newly introduced method based on Markov chains, which identifies spurious cycles among the results of the synchronous simulation. Based on this method, we present here the results of the analysis of the cholesterol biosynthesis pathway and its physiological regulation by the Sterol Response Element Binding Proteins (SREBPs), as well as the modeling of the action of statins, inhibitor drugs, on this pathway. The in silico experiments show the blockade of the cholesterol endogenous synthesis by statins and its regulation by SREPBs, in full agreement with the known biochemical features of the pathway.
Conclusion: We believe that the method described here to identify spurious cycles opens new routes to compute large and biologically relevant models, thanks to the computational efficiency of synchronous simulation. Furthermore, to the best of our knowledge, we present here the first dynamic systems biology model of the human cholesterol pathway and several of its key regulatory control elements, hoping it would provide a good basis to perform in silico experiments and confront the resulting properties with published and experimental data. The model of the cholesterol pathway and its regulation, along with Boolean formulae used for simulation are available on our web site http://Bioinformaticsu613.free.fr . Graphical results of the simulation are also shown online. The SBML model is available in the BioModels database (http://www.ebi.ac.uk/biomodels/).

Curators comment: To make this model valid SBML, we had to put the BooleanLaws tags in the reactions' annotations into an ancillary namespace called http://kervizic/BooleanLaws .

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Format
SBML (L2V3)
Related Publication
  • Dynamical modeling of the cholesterol regulatory pathway with Boolean networks.
  • Kervizic G, Corcos L
  • BMC systems biology , 0/ 2008 , Volume 2 , pages: 99
  • Inserm U613, Faculté de Médecine, Université de Bretagne Occidentale, Brest, FRANCE. gwenael.kervizic@univ-brest.fr
  • BACKGROUND: Qualitative dynamics of small gene regulatory networks have been studied in quite some details both with synchronous and asynchronous analysis. However, both methods have their drawbacks: synchronous analysis leads to spurious attractors and asynchronous analysis lacks computational efficiency, which is a problem to simulate large networks. We addressed this question through the analysis of a major biosynthesis pathway. Indeed the cholesterol synthesis pathway plays a pivotal role in dislypidemia and, ultimately, in cancer through intermediates such as mevalonate, farnesyl pyrophosphate and geranyl geranyl pyrophosphate, but no dynamic model of this pathway has been proposed until now. RESULTS: We set up a computational framework to dynamically analyze large biological networks. This framework associates a classical and computationally efficient synchronous Boolean analysis with a newly introduced method based on Markov chains, which identifies spurious cycles among the results of the synchronous simulation. Based on this method, we present here the results of the analysis of the cholesterol biosynthesis pathway and its physiological regulation by the Sterol Response Element Binding Proteins (SREBPs), as well as the modeling of the action of statins, inhibitor drugs, on this pathway. The in silico experiments show the blockade of the cholesterol endogenous synthesis by statins and its regulation by SREPBs, in full agreement with the known biochemical features of the pathway. CONCLUSION: We believe that the method described here to identify spurious cycles opens new routes to compute large and biologically relevant models, thanks to the computational efficiency of synchronous simulation. Furthermore, to the best of our knowledge, we present here the first dynamic systems biology model of the human cholesterol pathway and several of its key regulatory control elements, hoping it would provide a good basis to perform in silico experiments and confront the resulting properties with published and experimental data. The model of the cholesterol pathway and its regulation, along with Boolean formulae used for simulation are available on our web site http://Bioinformaticsu613.free.fr. Graphical results of the simulation are also shown online. The SBML model is available in the BioModels database http://www.ebi.ac.uk/biomodels/ with submission ID: MODEL0568648427.
Contributors
Gwenael Kervizic

Metadata information

is
BioModels Database MODEL0568648427
isDescribedBy
PubMed 19025648
hasTaxon
Taxonomy Homo sapiens
isVersionOf
hasProperty
Mathematical Modelling Ontology Ordinary differential equation model
Curation status
Non-curated
  • Model originally submitted by : Gwenael Kervizic
  • Submitted: 02-Dec-2008 10:58:47
  • Last Modified: 26-Feb-2009 18:06:25
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 26-Feb-2009 18:06:25
    • Submitted by: Gwenael Kervizic
    • With comment: Current version of Kervizic2008_Cholesterol_SREBP
  • Version: 1 public model Download this version
    • Submitted on: 02-Dec-2008 10:58:47
    • Submitted by: Gwenael Kervizic
    • With comment: Original import of Kervizic_Cholesterol_SREBP