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Combined logical and data-driven models for linking signalling pathways to cellular response
Melas, Ioannis N
, Mitsos, Alexander
, Messinis, Dimitris E
, Weiss, Thomas S.
und Alexopoulos, Leonidas G
(2011)
Combined logical and data-driven models for linking signalling pathways to cellular response.
BMC Systems Biology 5, S. 107.
Veröffentlichungsdatum dieses Volltextes: 16 Aug 2024 10:44
Artikel
DOI zum Zitieren dieses Dokuments: 10.5283/epub.58916
Zusammenfassung
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, ...
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.
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| Dokumentenart | Artikel | ||||
| Titel eines Journals oder einer Zeitschrift | BMC Systems Biology | ||||
| Verlag: | BMC | ||||
|---|---|---|---|---|---|
| Ort der Veröffentlichung: | LONDON | ||||
| Band: | 5 | ||||
| Seitenbereich: | S. 107 | ||||
| Datum | 5 Juli 2011 | ||||
| Institutionen | Medizin > Lehrstuhl für Kinder- und Jugendmedizin | ||||
| Identifikationsnummer |
| ||||
| Stichwörter / Keywords | GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITOR; HEPATOCELLULAR-CARCINOMA; TUMOR-CELLS; NETWORKS; TRANSDUCTION; INFLAMMATION; CANCER; HEPATOCYTES; ACTIVATION; | ||||
| Dewey-Dezimal-Klassifikation | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin | ||||
| Status | Veröffentlicht | ||||
| Begutachtet | Ja, diese Version wurde begutachtet | ||||
| An der Universität Regensburg entstanden | Ja | ||||
| URN der UB Regensburg | urn:nbn:de:bvb:355-epub-589160 | ||||
| Dokumenten-ID | 58916 |
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