The Virtual Liver Network: A systems biology approach to liver function and physiology

Subject of this project is to explore the physiology and functionality of the liver at different scales (cellular, intercellular, lobular and organ level) with the integration of these scales as an aim. Detoxification as a major task plays thereby an important role. The group of Prof. Zell is involved in dynamic modeling of signaling pathways and the reconstruction of transcriptional regulatory networks within subprojects A3.4 and B5.

A3.4: Linking signalling to metabolic functions

Partners: Rolf Gebhardt (University of Leipzig), Ute Hofmann (Dr. Margarete Fischer-Bosch - Institute for Clinical Pharmacology), Thomas Joos (Natural and Medical Sciences Institute at the University of Tuebingen), Steffen Klamt (Max-Planck-Institute for Dynamics of Complex Technical Systems), Martina Muckenthaler (Molecular Medicine at the University of Heidelberg), Ulrich M. Zanger (Dr. Margarete Fischer-Bosch - Institute for Clinical Pharmacology).

Modeling the linkage between signaling pathways and metabolic functions of central- and iron-metabolism as well as drug biotransformation based on systematic and time-dependent gene expression, phosphoprotein, and metabolomic data from human/mouse hepatocyte perturbation experiments.

Liver cells are highly responsive to many different signalling molecules, including endogenous hormones, growth factors, and cytokines, as well as diverse exogenous substances like drugs, plant toxins or environmental chemicals that provide the cells with information on the surrounding conditions and their changes. Complex networks of interdependent signal transduction pathways mediate the sensing and processing of stimuli in molecular circuits that detect, amplify, and integrate these diverse signals to generate responses in gene expression, that ultimately lead to changes in metabolic rates and fluxes. Modelling the link between signalling and metabolism is one of the major challenges in current systems biology since multiple heterogeneous levels of biological complexity, i.e., signalling cascades and transcriptional regulatory networks need to be considered. In recent years, several methods for the structural reconstruction and modelling of signalling pathways as well as transcriptional regulatory networks have been developed. However, concepts for the integrated modelling of these different levels of complexity are still lacking. In this subproject novel approaches leading towards an integrative reconstruction and logical modelling of the link between signalling and metabolism will be pursued for major signalling pathways involved in the regulation of intermediary metabolism as well as drug biotransformation functions in hepatocytes.

B5: Impact of cell-cell communication on detoxifying functions in hepatocytes

Partners: Dieter Häussinger (Department of Gastroenterology, Hepatology and Infectiology - University of Düsseldorf), Ute Hofmann (Dr. Margarete Fischer-Bosch - Institute for Clinical Pharmacology), Thomas Joos (Natural and Medical Sciences Institute at the University of Tuebingen), Jens Timmer (Institute of Physics University of Freiburg), Ulrich M. Zanger (Dr. Margarete Fischer-Bosch - Institute for Clinical Pharmacology).

Characterization and dynamic modelling of the impact and selectivity of cytokines on transcription and activity of hepatic detoxification in the short-term (hours) and long-term (days) scale, based on time-series experiments in human hepatocytes.

It is well known that compromised drug detoxification capacity results from the acute phase reaction during inflammation, infection, and cancer. These lead to significant treatment limitations particularly in patients treated with cytotoxic drugs with narrow therapeutic window, necessitating drug dosage adjustment during therapy. We have shown, e.g., by analyzing human liver samples from patients with elevated acute phase response protein CRP, an up to 5 fold down regulation of the important CYP3A4 and effects on numerous other ADME genes. The regulation of cytochrome P450s, phase 2 enzymes and transporter proteins is mediated by various cytokines, secreted by macrophages or tumour cells. Furthermore, IFNs and IL2 are used in the therapy of various cancers and have the potential for drug-drug interactions. The major signal transduction pathways involved in the changes of drug detoxification capacity have only been clarified in few cases. Thus, project B.5 aims at comprehensively analysing and modelling the effects of various cytokines on expression and activity of the drug detoxification system.

Publications

[1] Roland Keller, Marcus Klein, Maria Thomas, Andreas Dräger, Ute Metzger, Markus F. Templin, Thomas O. Joos, Wolfgang E. Thasler, Andreas Zell, and Ulrich M. Zanger. Coordinating role of RXRα in downregulating hepatic detoxification during inflammation revealed by fuzzy-logic modeling. PLoS Computational Biology, 12(1):e1004431, January 2016. [ DOI | details | link ]
[2] Roland Keller. Simulation and optimization of logical and kinetic biochemical models. PhD thesis, University of Tuebingen, Tübingen, Germany, 2016. in press.
[3] Andreas Dräger, Daniel C. Zielinski, Roland Keller, Matthias Rall, Johannes Eichner, Bernhard O. Palsson, and Andreas Zell. SBMLsqueezer 2: Context-sensitive creation of kinetic equations in biochemical networks. BMC Systems Biology, 9(1):1-17, September 2015. [ DOI | details | link | pdf ]
[4] Nicolas Rodriguez, Alex Thomas, Leandro Watanabe, Ibrahim Y. Vazirabad, Victor Kofia, Harold F. Gómez, Florian Mittag, Jakob Matthes, Jan D. Rudolph, Finja Wrzodek, Eugen Netz, Alexander Diamantikos, Johannes Eichner, Roland Keller, Clemens Wrzodek, Sebastian Fröhlich, Nathan E. Lewis, Chris J. Myers, Nicolas Le Novère, Bernhard Ø. Palsson, Michael Hucka, and Andreas Dräger. JSBML 1.0: providing a smorgasbord of options to encode systems biology models. Bioinformatics, June 2015. [ DOI | arXiv | details | link | pdf ]
[5] Stefan Ohrnberger, Abhishek Thavamani, Albert Braeuning, Daniel B Lipka, Milen Kirilov, Robert Geffers, Stella E Authenrieth, Michael Römer, Andreas Zell, Michael Bonin, Michael Schwarz, Günther Schütz, Peter Schirmacher, Christoph Plass, Thomas Longerich, and Alfred Nordheim. Dysregulated serum response factor triggers formation of hepatocellular carcinoma. Hepatology, March 2015. [ DOI | details | link | pdf ]
[6] Alexander Dörr, Roland Keller, Andreas Zell, and Andreas Dräger. SBMLsimulator: a Java tool for model simulation and parameter estimation in systems biology. Computation, 2(4):246-257, December 2014. [ DOI | details | link | link ]
[7] Johannes Eichner, Yvonne Heubach, Manuel Ruff, Hella Kohlhof, Stefan Strobl, Barbara Mayer, Michael Pawlak, Markus F. Templin, and Andreas Zell. RPPApipe: A pipeline for the analysis of reverse-phase protein array data. BioSystems, June 2014. [ DOI | details | link | pdf ]
[8] Claudine Chaouiya, Duncan Bérenguier, Sarah M. Keating, Aurélien Naldi, Martijn P. van Iersel, Nicolas Rodriguez, Andreas Dräger, Finja Büchel, Thomas Cokelaer, Bryan Kowal, Benjamin Wicks, Emanuel Gonçalves, Julien Dorier, Michel Page, Pedro T. Monteiro, Axel von Kamp, Ioannis Xenarios, Hidde de Jong, Michael Hucka, Steffen Klamt, Dennis Thierffry, Nicolas Le Novère, Julio Saez-Rodriguez, and Tomáš Helikar. SBML Qualitative Models: a model representation format and infrastructure to foster interactions between qualitative modelling formalisms and tools. BMC Systems Biology, 7(1):135, December 2013. [ DOI | arXiv | details | link | pdf ]
[9] Johannes Eichner, Florian Topf, Andreas Dräger, Clemens Wrzodek, Dierk Wanke, and Andreas Zell. TFpredict and SABINE: Sequence-Based Prediction of Structural and Functional Characteristics of Transcription Factors. PLoS ONE, 8(12):e82238, December 2013. [ DOI | details | link | link ]
[10] Finja Büchel, Nicolas Rodriguez, Neil Swainston, Clemens Wrzodek, Tobias Czauderna, Roland Keller, Florian Mittag, Michael Schubert, Mihai Glont, Martin Golebiewski, Martijn van Iersel, Sarah M. Keating, Matthias Rall, Michael Wybrow, Henning Hermjakob, Michael Hucka, Douglas B Kell, Wolfgang Müller, Pedro Mendes, Andreas Zell, Claudine Chaouiya, Julio Saez-Rodriguez, Falk Schreiber, Camille Laibe, Andreas Dräger, and Nicolas Le Novère. Path2Models: large-scale generation of computational models from biochemical pathway maps. BMC Systems Biology, 7(1):116, November 2013. [ DOI | details | link | pdf ]
[11] Andreas Dräger and Hannes Planatscher. Encyclopedia of Systems Biology, chapter Metabolic Networks, pages 1249-1251. Springer-Verlag, Springer New York Heidelberg Dorodrecht London, August 2013. [ DOI | details | link ]
[12] Andreas Dräger and Hannes Planatscher. Encyclopedia of Systems Biology, chapter Parameter Estimation, Metabolic Network Modeling, pages 1627-1631. Springer-Verlag, Springer New York Heidelberg Dorodrecht London, August 2013. [ DOI | details | link ]
[13] Roland Keller, Alexander Dörr, Akito Tabira, Akira Funahashi, Michael J. Ziller, Richard Adams, Nicolas Rodriguez, Nicolas Le Novère, Noriko Hiroi, Hannes Planatscher, Andreas Zell, and Andreas Dräger. The systems biology simulation core algorithm. BMC Systems Biology, 7:55, July 2013. [ DOI | details | link | pdf ]
[14] Sebastian Vlaic, Bianca Hoffmann, Peter Kupfer, Michael Weber, and Andreas Dräger. GRN2SBML: Automated encoding and annotation of inferred gene regulatory networks complying with SBML. Bioinformatics, 29:2216-2217, June 2013. [ DOI | details | link | pdf ]
[15] Clemens Wrzodek. Inference and integration of biochemical networks with multilayered omics data. PhD thesis, University of Tuebingen, Tübingen, Germany, June 2013. [ details | link ]
[16] Clemens Wrzodek, Finja Büchel, Manuel Ruff, Andreas Dräger, and Andreas Zell. Precise generation of systems biology models from KEGG pathways. BMC Systems Biology, 7(1):15, January 2013. [ DOI | details | link | pdf ]
[17] Finja Büchel, Clemens Wrzodek, Florian Mittag, Andreas Dräger, Johannes Eichner, Nicolas Rodriguez, Nicolas Le Novère, and Andreas Zell. Qualitative translation of relations from BioPAX to SBML qual. Bioinformatics, 28(20):2648-2653, August 2012. [ DOI | details | link | pdf ]
[18] Matthias König, Andreas Dräger, and Hermann-Georg Holzhütter. CySBML: a Cytoscape plugin for SBML. Bioinformatics, 28(18):2402-2403, July 2012. [ DOI | details | link ]
[19] Adrian Schröder. Inference of gene-regulatory networks in primary human hepatocytes. PhD thesis, University of Tuebingen, Tübingen, Germany, November 2011. [ details | link ]
[20] Mélanie Courtot, Nick Juty, Christian Knüpfer, Dagmar Waltemath, Anna Zhukova, Andreas Dräger, Michel Dumontier, Andrew Finney, Martin Golebiewski, Janna Hastings, Stefan Hoops, Sarah M. Keating, Douglas B. Kell, Samuel Kerrien, James Lawson, Allyson Lister, James Lu, Rainer Machne, Pedro Mendes, Matthew Pocock, Nicolas Rodriguez, Alice Villéger, Darren J. Wilkinson, Sarala Wimalaratne, Camille Laibe, Michael Hucka, and Nicolas Le Novère. Controlled vocabularies and semantics in systems biology. Molecular Systems Biology, 7(1):543, September 2011. [ DOI | details | link | pdf ]
[21] Adrian Schröder, Kathrin Klein, Stefan Winter, Matthias Schwab, Michael Bonin, Andreas Zell, and Ulrich M. Zanger. Genomics of ADME gene expression: mapping expression quantitative trait loci relevant for absorption, distribution, metabolism and excretion of drugs in human liver. The Pharmacogenomics Journal, pages 1473-1150, September 2011. [ DOI | details | link | pdf ]
[22] Adrian Schröder, Johannes Wollnik, Clemens Wrzodek, Andreas Dräger, Michael Bonin, Oliver Burk, Maria Thomas, Wolfgang E. Thasler, Ulrich M. Zanger, and Andreas Zell. Inferring statin-induced gene regulatory relationships in primary human hepatocytes. Bioinformatics, 27(18):2473-2477, July 2011. [ DOI | details | link | pdf ]
[23] Andreas Dräger, Nicolas Rodriguez, Marine Dumousseau, Alexander Dörr, Clemens Wrzodek, Nicolas Le Novère, Andreas Zell, and Michael Hucka. JSBML: a flexible Java library for working with SBML. Bioinformatics, 27(15):2167-2168, June 2011. [ DOI | details | link | pdf ]
[24] Adrian Schröder, Clemens Wrzodek, Johannes Wollnik, Andreas Dräger, Dierk Wanke, Kenneth W. Berendzen, and Andreas Zell. Inferring transcriptional regulators for sets of co-expressed genes by multi-objective evolutionary optimization. In IEEE Congress on Evolutionary Computation (CEC 2011), New Orleans, USA, June 2011. IEEE. [ DOI | details | link | pdf ]
[25] Andreas Dräger. Computational Modeling of Biochemical Networks. PhD thesis, University of Tuebingen, Tübingen, Germany, January 2011. [ details | link ]

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Contact: Andreas Dräger, office C313, phone +49-7071-29-78982, andreas.draeger@uni-tuebingen.de