Modeling of the TNF - TNF receptor signaling network

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Tumor necrosis factor (TNF) receptor-1 (TNFR1) and TNFR2 coexpressing cells with the potential to produce TNF, e.g. T-cells, macrophages, dendritic cells and fibroblasts, are of great importance for homeostasis of the immune system in general and have an overwhelming role in many autoimmune diseases. We and others have shown that the activity of signaling pathways engaged by TNFR1 and TNFR2 as well as the production of their stimulating ligands (TNFR1: soluble and membrane TNF, TNFR2: membrane TNF) are integrated by a variety of connected positive and negative feedback loops. The quality (inflammation versus apoptosis), duration and amplitude of the cellular TNF response are therefore currently not predictable. The rational development and refinement of therapy concepts relying on interference with the function of the TNF-TNF receptor system are therefore not feasible yet and instead base to considerable extent on “trial and error”. It is the aim of this project to develop a mathematical model describing TNF-induced cellular responses of TNFR1 and TNFR2 coexpressing TNF producing cells under special consideration of the regulatory principles revealed in our previous work. The modeling work will be accompanied by experimental work to verify the predictive power of the model and yet not available crucial biochemical parameters of relevance for the modeling approach will be determined.