Division of Systems Biology of Signal Transduction
Prof. Dr. Ursula Klingmüller
The goal of the division is to gain insights into molecular mechanisms that regulate cellular decisions and to address their impact on behavior at the tissue and organ level. When these control mechanisms fail, cancer and other diseases arise. Cellular responses are regulated by a multitude of extracellular signals received by cell surface receptors. Within cells the information is processed through complex intracellular signaling networks that in turn impinge on gene regulation and affect metabolism to finally coordinate physiological responses such as proliferation, survival and differentiation. These responses operate on very different time scales ranging from minutes to hours and days. Thus, it is essential to examine key dynamic properties of biological systems, which can be addressed by combining the generation of quantitative time-resolved data with mathematical modeling. Data-based mathematical models enable rapid testing of hypotheses to uncover deregulation in cancer and to predict strategies of intervention in diseases.
In close collaboration with modeling partners, methods for quantitative analysis of signaling networks were developed and multiple dynamic pathway models were established yielding unexpected insights into regulatory mechanisms of signaling pathways. The main projects of the division address:
- Unraveling principal mechanisms of erythropoietin (Epo)-mediated cellular decisions in the hematopoietic system.
- Bridging from the cellular to the whole organ level during liver regeneration.
- Insights into altered regulation in cancer and prediction of strategies for efficient intervention in diseases (cancer, drug-induced liver injury, viral infection).
This knowledge will be used to establish integrated models of signaling pathways, to link them to gene regulation as well as cell-cell communication and to include cell cycle progression and cell survival. Finally, integration into multi-scale models and whole body models is aspired. Translational aspects are strengthened through intensive collaborations with clinical partners and companies in the frame of large third party funded research networks.
M. Schilling, T. Maiwald, S. Hengl, D. Winter, C. Kreutz, W. Kolch, W. D. Lehmann, J. Timmer, and U. Klingmüller. Theoretical and experimental analysis links isoform-specific ERK signalling to cell fate decisions, Mol Sys Biol (2009), 334:119-36.
V. Becker, M. Schilling, J. Bachmann, U. Baumann, A. Raue, T. Maiwald, J. Timmer, U. Klingmüller. Covering a broad dynamic range: information processing at the erythropoietin receptor. Science (2010), 328:1404-08.
Raia V, Schilling M, Böhm M, Hahn B, Kowarsch A, Raue A, Sticht C, Bohl S, Saile M, Möller P, Gretz N, Timmer J, Theis F, Lehmann WD, Lichter P, Klingmüller U. Dynamic mathematical modeling of IL13-induced signaling in Hodgkin and primary mediastinal B-cell lymphoma allows prediction of therapeutic targets. Cancer Res. 2011 Feb 1;71(3):693-704.
Bachmann J, Raue A, Schilling M, Böhm ME, Kreutz C, Kaschek D, Busch H, Gretz N, Lehmann WD, Timmer J, Klingmüller U. Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range. Mol Syst Biol. 2011 7:516