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Dynamic Analysis of Integrated Signaling, Metabolic, and Regulatory Networks 英文参考文献
DynamicAnalysisofIntegratedSignaling,Metabolic,and
RegulatoryNetworks
JongMinLee.¤a,ErwinP.Gianchandani.,JamesA.Eddy¤b,JasonA.Papin*
DepartmentofBiomedicalEngineering,UniversityofVirginiaHealthSystem,Charlottesville,Virginia,UnitedStatesofAmerica
Abstract
Extracellular cues affect signaling, metabolic, and regulatory processes to elicit cellular responses. Although intracellular
signaling,metabolic,andregulatorynetworksarehighlyintegrated,previousanalyseshavelargelyfocusedonindependent
processes (e.g., metabolism) without considering the interplay that exists among them. However, there is evidence that
manydiseasesarisefrommultifunctionalcomponentswithrolesthroughoutsignaling,metabolic,andregulatorynetworks.
Therefore,inthis study,weproposeafluxbalanceanalysis(FBA)–based strategy,referredtoasintegrateddynamic FBA
(idFBA),thatdynamicallysimulatescellularphenotypesarisingfromintegratednetworks.TheidFBAframeworkrequiresan
integrated stoichiometric reconstruction of signaling, metabolic, and regulatory processes. It assumes quasi-steady-state
conditions for ‘‘fast’’ reactions and incorporates ‘‘slow’’ reactions into the stoichiometric formalism in a time-delayed
manner.ToassesstheefficacyofidFBA,wedevelopedaprototypicintegratedsystemcomprisingsignaling,metabolic,and
regulatoryprocesseswithnetworkfeaturescharacteristicofactualsystemsandincorporatingkineticparametersbasedon
typicaltimescalesobservedinliterature. idFBAwasappliedtotheprototypic system,whichwasevaluatedfordifferent
environments and gene regulatory rules. In addition, we applied the idFBA framework in a similar manner to a
representative module of the single-cell eukaryotic organism Saccharomyces cerevisiae. Ultimately, idFBA facilitated
quantitative,dynamicanalysisofsystemiceffectsofextracellularcuesoncellularphenotypesandgeneratedcomparable
time-course predictions when contrasted with an equivalent kinetic model. Since idFBA solves a linear programming
problemanddoesnotrequireanexhaustivelisto
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