C2_Cell Cycle
Cell Cycle: Proliferation Control in Hepatocytes
PD Dr. Ursula Klingmüller (PL), Stephanie Müller (PhD student)
MPI for Dynamics of Complex Technical Systems (Magdeburg)
Prof. Dr. Ernst Dieter Gilles (PL), Jeremy Huard (PhD student)
Institute for Theoretical Biology (Humboldt-University of Berlin)
Prof. Dr. Hans-Peter Herzel, Anuradha Chauhan (PhD student), Dr. Stefan Legewie (PhD)
Project summary:
Liver regeneration is orchestrated by highly regulated signaling pathways, a sequential activation of regulatory loops, and a well-controlled signal termination to guarantee constant organ size. In this project we develop in a stepwise manner a model that integrates theoretical aspects and experimental results from specific signaling cascades. The integrated model can be incorporated into the multi-scale approach in project C3. On one hand we will continue the bottom-up modeling with a detailed representation of the molecular network. Such a detailed model of fast posttranscriptional regulation will allow to construct the interface to signaling pathways activated by IL-6, TNF-alpha, HGF, EGF or insulin.
On the other hand, we will extend the top-down approach focused on slow transcriptional processes, where fast regulations such as phosphorylation cascades are eliminated from the system. The current model version accurately reproduces experimentally measured kinetics of various signalling intermediates and that of DNA synthesis in hepatocytes for varying degrees of liver damage, in both wildtype and knockout backgrounds. These model simulations will be related to expression profiles and promoter analyses in collaboration with Projects B8 and B9.
In order to describe cell growth inhibition the TGF-beta pathway will be included in extended model versions in collaboration with Project B6.
Moreover, we will study cross-talk to pro- and anti-apoptotic pathways together with Project C1. Finally, we will consider stochastic aspects of cell cycle regulation and the role of cytokine gradients as a prerequisite of Project C3. Simulations of the integrated model will be compared to experimental data from hepatocytes of hepatectomized animals co-stimulated with priming factors and growth factors in collaboration with R. Gebhardt (Cell Biology Platform).