Combined logical and data-driven models for linking signalling pathways to cellular response.
| Autor: | Melas IN; Dept of Mechanical Engineering, National Technical University of Athens, 15780 Zografou, Greece., Mitsos A, Messinis DE, Weiss TS, Alexopoulos LG |
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| Jazyk: | angličtina |
| Zdroj: | BMC systems biology [BMC Syst Biol] 2011 Jul 05; Vol. 5, pp. 107. Date of Electronic Publication: 2011 Jul 05. |
| DOI: | 10.1186/1752-0509-5-107 |
| Abstrakt: | Background: Signalling pathways are the cornerstone on understanding cell function and predicting cell behavior. Recently, logical models of canonical pathways have been optimised with high-throughput phosphoproteomic data to construct cell-type specific pathways. However, less is known on how signalling pathways can be linked to a cellular response such as cell growth, death, cytokine secretion, or transcriptional activity. Results: In this work, we measure the signalling activity (phosphorylation levels) and phenotypic behavior (cytokine secretion) of normal and cancer hepatocytes treated with a combination of cytokines and inhibitors. Using the two datasets, we construct "extended" pathways that integrate intracellular activity with cellular responses using a hybrid logical/data-driven computational approach. Boolean logic is used whenever a priori knowledge is accessible (i.e., construction of canonical pathways), whereas a data-driven approach is used for linking cellular behavior to signalling activity via non-canonical edges. The extended pathway is subsequently optimised to fit signalling and behavioural data using an Integer Linear Programming formulation. As a result, we are able to construct maps of primary and transformed hepatocytes downstream of 7 receptors that are capable of explaining the secretion of 22 cytokines. Conclusions: We developed a method for constructing extended pathways that start at the receptor level and via a complex intracellular signalling pathway identify those mechanisms that drive cellular behaviour. Our results constitute a proof-of-principle for construction of "extended pathways" that are capable of linking pathway activity to diverse responses such as growth, death, differentiation, gene expression, or cytokine secretion. (© 2011 Melas et al; licensee BioMed Central Ltd.) |
| Databáze: | MEDLINE |
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