   Robustness-based model validation of an apoptosis signalling network modelSchliemann, Monica  ; ; Bullinger, Eric in Proceedings of the 16th IFAC Symposium on System Identification, Brussels, Belgium, 11–13 July 2012 (2012) Models of intracellular biochemical reaction networks are difficult to parameterise due to the low number of quantitative time series experimental values. Therefore, model validation or invalidation plays ... [more ▼] Models of intracellular biochemical reaction networks are difficult to parameterise due to the low number of quantitative time series experimental values. Therefore, model validation or invalidation plays an important role, as it allows to check qualitatively whether a model structure is suited or not to reproduce qualitatively the experimental findings. This paper analyses the robustness of an experimentally validated polynomial differential equation model of TNF-induced pro-and anti-apoptotic signalling. The bistability of the median model is shown robust to large single parameter variations. Only two parameters (XIAP and Procaspase-3 production rates) are shown to be fragile, in particular when changed simultaneously. Therefore, the model seems valid from the point of view of robustness analysis of the bistability. Many biological experiments quantify average concentrations or the percentage of viable cells, while other methods such as microscopy-based experiments observe single cells. The integration of single cell and cell population behaviour of TNF-induced pro- and anti-apoptotic signalling has been achieved via a cell ensemble model, whose robustness is also analysed here. We show that within the cell population there are cells with not only quantitative differences, but also qualitative ones. In particular, all cells are not bistable. The degree of robustness applicable for the median cell is expanded to combine mono- and bistable models. This measure, applied solely to the two-dimensional subspace of fragile parameters, is shown to correlate well with the time of death. While robustness of bistability can serve for model validation of the median cell model, it cannot for the model of the cell population. [less ▲] Detailed reference viewed: 11 (5 ULg) Heterogeneity Reduces Sensitivity of Cell Death for TNF-StimuliSchliemann, Monica ; Bullinger, Eric ; et alin BMC Systems Biology (2011), 5 Background Apoptosis is a form of programmed cell death essential for the maintenance of homeostasis and the removal of potentially damaged cells in multicellular organisms. By binding its cognate ... [more ▼] Background Apoptosis is a form of programmed cell death essential for the maintenance of homeostasis and the removal of potentially damaged cells in multicellular organisms. By binding its cognate membrane receptor, TNF receptor type 1 (TNF-R1), the proinflammatory cytokine Tumor Necrosis Factor (TNF) activates pro-apoptotic signaling via caspase activation, but at the same time also stimulates nuclear factor kappaB (NF-kappaB)-mediated survival pathways. Differential dose-response relationships of these two major TNF signaling pathways have been described experimentally and using mathematical modeling. However, the quantitative analysis of the complex interplay between pro- and anti-apoptotic signaling pathways is an open question as it is challenging for several reasons: the overall signaling network is complex, various time scales are present, and cells respond quantitatively and qualitatively in a heterogeneous manner. Results This study analyzes the complex interplay of the crosstalk of TNF-R1 induced pro- and anti-apoptotic signaling pathways based on an experimentally validated mathematical model. The mathematical model describes the temporal responses on both the single cell level as well as the level of a heterogeneous cell population, as observed in the respective quantitative experiments using TNF-R1 stimuli of different strengths and durations. Global sensitivity of the heterogeneous population was quantified by measuring the average gradient of time of death versus each population parameter. This global sensitivity analysis uncovers the concentrations of Caspase-8 and Caspase-3, and their respective inhibitors BAR and XIAP, as key elements for deciding the cell's fate. A simulated knockout of the NF-kappaB-mediated anti-apoptotic signaling reveals the importance of this pathway for delaying the time of death, reducing the death rate in the case of pulse stimulation and significantly increasing cell-to-cell variability. Conclusions Cell ensemble modeling of a heterogeneous cell population including a global sensitivity analysis presented here allowed us to illuminate the role of the different elements and parameters on apoptotic signaling. The receptors serve to transmit the external stimulus; procaspases and their inhibitors control the switching from life to death, while NF-kappaB enhances the heterogeneity of the cell population. The global sensitivity analysis of the cell population model further revealed an unexpected impact of heterogeneity, i.e. the reduction of parametric sensitivity. [less ▲] Detailed reference viewed: 58 (16 ULg)Review of three Recent Books on the Boundary of Bioinformatics and Systems BiologyBullinger, Eric ; Schliemann, Monica in BioMedical Engineering OnLine (2010), 9(1), 33 Detailed reference viewed: 14 (3 ULg)A Systems Biology Approach to Apoptosis SignallingSchliemann, Monica ; ; Bullinger, Eric Scientific conference (2009, November 17) Detailed reference viewed: 5 (0 ULg)A Systems Biology Approach to Apoptosis SignallingSchliemann, Monica ; ; et alScientific conference (2009, June 17) Detailed reference viewed: 1 (0 ULg)A Systems Biology Approach to Apoptosis SignallingSchliemann, Monica ; ; Bullinger, Eric Conference (2009, May 15) Detailed reference viewed: 2 (0 ULg)A Systems Biology Approach to Apoptosis SignallingSchliemann, Monica ; ; Bullinger, Eric Scientific conference (2009, April 22) Detailed reference viewed: 3 (0 ULg)Modelling and parameter estimation for heterogeneous cell populations; ; Schliemann, Monica et alPoster (2009) Detailed reference viewed: 12 (0 ULg)Estimation of biochemical network parameter distributions in cell populations; ; Schliemann, Monica et alPoster (2009) Detailed reference viewed: 18 (0 ULg)A System Understanding of TNF-α Induced Apoptotic and Antiapoptotic Signalling: Combining Single Cell and Population Modelling with Dynamic and Quantitative ExperimentsSchliemann, Monica ; ; Bullinger, Eric Poster (2009) Detailed reference viewed: 7 (0 ULg)TNF-α induced Apoptotic and Anti-apoptotic Signalling: A Systems Biology Approach combining Dynamic and Quantitative Experiments with Mathematical ModellingSchliemann, Monica ; ; et alPoster (2008, August) Detailed reference viewed: 3 (0 ULg)TNF-α Induced Apoptopic and Anti-apoptopic Signalling: A Systems Biology Approach Combining Dynamic and Quantitative Expriments with Mathematical ModellingSchliemann, Monica ; ; Bullinger, Eric Conference (2008, March 28) Detailed reference viewed: 4 (0 ULg)The TNF receptor signalling network: Modular modelling and cell-type specific analysis; ; Schliemann, Monica et alPoster (2008) Detailed reference viewed: 14 (0 ULg)Mathematical modelling of TNF- induced anti-apoptotic signalling pathways in mammalian cells based on dynamic and quantitative experimentsSchliemann, Monica ; ; et alin Proc. 2nd Foundations of Systems Biology in Engineering FOSBE 2007 (2007, September) 2nd Foundations of Systems Biology in Engineering FOSBE 2007 Detailed reference viewed: 13 (2 ULg)The question of parameter identifiability for biochemical reaction networks considering the NF- κB signal transduction pathway; ; Schliemann, Monica et alin Proc. 2nd Foundations of Systems Biology in Engineering FOSBE 2007 (2007) Detailed reference viewed: 17 (0 ULg)Mathematical Modelling of TNF Induced Apoptotic and Anti-apoptotic Crosstalk in Mammalian CellsSchliemann, Monica ; ; Bullinger, Eric et alPoster (2006, July) Detailed reference viewed: 3 (2 ULg)Mathematical Modelling of TNF induced apoptosis and anti-apoptotic crosstalk in mammalian cells; Schliemann, Monica ; et alPoster (2005) Detailed reference viewed: 3 (0 ULg) |
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