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Modeling system states in liver cells: survival, apoptosis and their modifications in response to viral infection

Abstract:

BACKGROUND: The decision pro- or contra apoptosis is complex, involves a number of different inputs, and is central for the homeostasis of an individual cell as well as for the maintenance and regeneration of the complete organism. RESULTS: This study centers on Fas ligand (FasL)-mediated apoptosis, and a complex and internally strongly linked network is assembled around the central FasL-mediated apoptosis cascade. Different bioinformatical techniques are employed and different crosstalk possibilities including the integrin pathway are considered. This network is translated into a Boolean network (74 nodes, 108 edges). System stability is dynamically sampled and investigated using the software SQUAD. Testing a number of alternative crosstalk possibilities and networks we find that there are four stable system states, two states comprising cell survival and two states describing apoptosis by the intrinsic and the extrinsic pathways, respectively. The model is validated by comparing it to experimental data from kinetics of cytochrome c release and caspase activation in wildtype and Bid knockout cells grown on different substrates. Pathophysiological modifications such as input from cytomegalovirus proteins M36 and M45 again produces output behavior that well agrees with experimental data. CONCLUSION: A network model for apoptosis and crosstalk in hepatocytes shows four different system states and reproduces a number of different conditions around apoptosis including effects of different growth substrates and viral infections. It produces semi-quantitative predictions on the activity of individual nodes, agreeing with experimental data. The model (SBML format) and all data are available for further predictions and development.

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BMC Syst Biol
BMC Syst Biol 3: 97
12th May 2009

Nicole Philippi, Dorothee Walter, Rebekka Schlatter, Karine Ferreira, Michael Ederer, Oliver Sawodny, Jens Timmer, Christoph Borner, Thomas Dandekar

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[Karine Ferreira] [Michael Ederer] [Oliver Sawodny] [Jens Timmer] [Christoph Borner]

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Views: 2529
  • Created: 3rd Dec 2010 at 10:01
  • Last updated: 24th Oct 2013 at 16:21

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