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Melas, Ioannis N ; Mitsos, Alexander ; Messinis, Dimitris E ; Weiss, Thomas S. ; Alexopoulos, Leonidas G

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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Details

DokumentenartArtikel
Titel eines Journals oder einer ZeitschriftBMC Systems Biology
Verlag:BMC
Ort der Veröffentlichung:LONDON
Band:5
Seitenbereich:S. 107
Datum5 Juli 2011
InstitutionenMedizin > Lehrstuhl für Kinder- und Jugendmedizin
Identifikationsnummer
WertTyp
10.1186/1752-0509-5-107DOI
Stichwörter / KeywordsGROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITOR; HEPATOCELLULAR-CARCINOMA; TUMOR-CELLS; NETWORKS; TRANSDUCTION; INFLAMMATION; CANCER; HEPATOCYTES; ACTIVATION;
Dewey-Dezimal-Klassifikation600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin
StatusVeröffentlicht
BegutachtetJa, diese Version wurde begutachtet
An der Universität Regensburg entstandenJa
URN der UB Regensburgurn:nbn:de:bvb:355-epub-589160
Dokumenten-ID58916

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