Systems Biology: Quantitative Modeling and Analysis of Cytokine-mediated Signal Transduction Considering Uncertain Data and Parameters

Signal transduction pathways are of essential importance for organisms to react to environmental changes, e.g. by regulating gene expression. One possible stimulus are cytokines that are involved in many inflammatory diseases. An important cytokine is Interleukin-6 (IL-6). Activation of the IL-6 signalling pathways lead to the initiation of the JAK/STAT pathway (Janus Kinase/Signal Transducer and Activator of Transcription) as well as the MAPK cascade (Mitogen Activated Protein Kinase). A deregulation of the described processes causes a variety of disease, e.g. rheumatoid arthritis, multiple sclerosis, disorders of the bone marrow and several types of tumors [1,2,3].
Mathematical modeling and analysis of the underlying mechanisms leading to the development of such diseases provide important insights into the cellular processes and related dysregulations. Furthermore, possible targets can be identified to develop suitable intervention strategies and to reduce serious effects of widespread diseases such as cancer.

Within the framework of a Bachelor/Master/Student/Diploma-thesis project, students may work on several topics and questions including (but not limited to):

• modeling and analysis of the cytokine-mediated signal transduction based on experimental data provided by our collaborators (Prof. Fred Schaper, OvGU-Magdeburg, Systems biology)
• parameter estimation, model discrimination and (in-)validation using set-based methods (as developed in our group [4])
• experimental design

For a successful project, the student should have

• basic knowledge of modeling techniques in systems biology
• good knowledge of systems and control theory
• good knowledge of MatLab.

Close collaboration with experimentalists (Prof. Schaper, OvGU Magdeburg) and with theoreticians in our group is expected.

Always possible

For further information or to apply, please contact Nadine Rudolph (nadine.rudolph@ovgu.de).

• [1] Rudolph, N., Meyer, T., Franzen, K., Garbers, C., Streif, S., Schaper, F., Dittrich, A. and Findeisen, R., A Two-level Approach for Fusing Early Signaling Events and Long Term Biological Responses. In International Symposium on Advanced Control of Chemical Processes (ADCHEM), pages 1229-1234, Whistler, Canada, June 2015.
• [2] Streif, S., Strobel, N. and Findeisen, R., Inner Approximations of Consistent Parameter Sets Via Constraint Inversion and Mixed-integer Linear Programming. In Proc. of the 12th IFAC Symposium on Computer Applications in Biotechnology (CAB), pages 326-331, Mumbai, India, December 2013.
• [3] Jones, A. V., Kreil, S., Zoi, K., Waghorn, K., Curtis, C., Zhang, L., Score, J., Seear, R., Chase, A. J., Grand, F. H., White, H., Zoi, C., Loukopoulos, D., Terpos, E., Vervessou, E. C., Schultheis, B., Emig, M., Ernst, T., Lengfelder, E., Hehlmann, R., Hochhaus, A., Oscier, D., Silver, R. T., Reiter, A., and Cross, N. C., Widespread occurence oft he JAK2 V617F mutation in chronic myeloproliferative disorders. Blood, 2005, Vol. 106, pp. 2162-2168
• [4] Lo, C. W., Chen, M. W., Hsiao, M., Wang, S., Chen, C. A., Hsiao, S. M., Chang, J. S., Lai, T. C., Rose-John, S., Kua, M. L., IL-6 trans-siganling in formation and progression of malignant ascites in ovarian cancer. Cancer Research, 2011, Vol. 71, pp. 424-434
• [5] Houssiau, A. F, Devogelaer, J.-P., Van Damme, J., Nagant De Deuxchaisnes, C., Van Snick, J., Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthitis&Rheumatism, 2005, Vol. 31, pp. 784-788
• [6] Rumschinski, P., Borchers, S., Bosio, S., Weismantel, R. & Findeisen, R., Set-based dynamical parameter estimation and model invalidation for biochemical reaction networks.BMC Syst Biol, 2010, Vol. 4, pp. 69

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