Parameter estimation in models combining signal transduction and metabolic pathways: the dependent input approach, Syst Biol

N.A.W. Riel, van, E.D. Sontag

Research output: Contribution to journalArticleAcademicpeer-review

32 Citations (Scopus)
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VBiological complexity and limited quantitative measurements pose severe challenges to standard engineering methodologies for modelling and simulation of genes and gene products integrated in a functional network. In particular, parameter quantification is a bottleneck, and therefore parameter estimation, identifiability, and optimal experiment design are important research topics in systems biology. An approach is presented in which unmodelled dynamics are replaced by fictitious `dependent inputs'. The dependent input approach is particularly useful in validation experiments, because it allows one to fit model parameters to experimental data generated by a reference cell type (`wild-type') and then test this model on data generated by a variation (`mutant'), so long as the mutations only affect the unmodelled dynamics that produce the dependent inputs. Another novel feature of the approach is in the inclusion of a priori information in a multi-objective identification criterion, making it possible to obtain estimates of parameter values and their variances from a relatively limited experimental data set. The pathways that control the nitrogen uptake fluxes in baker's yeast (Saccharomyces cerevisiae) have been studied. Well-defined perturbation experiments were performed on cells growing in steady-state. Time-series data of extracellular and intracellular metabolites were obtained, as well as mRNA levels. A nonlinear model was proposed and was shown to be structurally identifiable given data of its inputs and outputs. The identified model is a reliable representation of the metabolic system, as it could correctly describe the responses of mutant cells and different perturbations.
Original languageEnglish
Pages (from-to)263-274
JournalIEE Proceedings - Systems Biology
Issue number4
Publication statusPublished - 2006


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