C3_Multi Scale Modelling

Prof. Dr. Jan G. Hengstler (PL), Alexander Bauer (PhD student)

Interdisciplinary Center for Bioinformatics ([IZBI]-University of Leipzig) and INRIA (France)
Dr. rer. nat. habil. Dirk Drasdo (PL), Axel Krinner (PhD student), Stefan Höhme (PhD student)

Anatomy and Cell Biology(University of Ulm)
Prof. Dr. Harald Teutsch (PL)

Project summary:

Normal liver function as well as liver regeneration requires the interplay of the individual functional units on all levels of organization ranging from individual molecules to signal transduction, to gene-and metabolic networks, up to the spatial and functional pattern on the level of the tissue units such as liver lobules and liver lobes. Intoxication by alcohol or CCl 4 leads to loss of hepatocytes with concomitant restriction of liver function followed by the complex process of regeneration. An understanding of this process cannot be expected at the level of a single cell alone. The mechanisms that are responsible for a failure of the capability to restore the architecture of the liver lobule are largely unknown and hard to be accessed by experimental studies alone, since the experimental procedure only permits to take a snapshoot at the moment of preparation. This proposal aims at studying spatial-temporal liver regeneration processes after induction of liver damage by administration of alcohol and CCl 4, and after partial hepatectomy with and without administration of cytokines. It bases on a process chain of (i) in-vivo experiments, (ii) image processing of serial sections from regenerating liver lobules and (iii) simulation of the full regeneration process with a single-cell based computer model. The model focuses on a liver lobule. The knowledge of the cytokine effect on the regulation of the hepatocyte function and of the hepatocyte polarity serve to determine potential model assumptions of cell-environment interaction, cell migration, proliferation, apoptosis and cell differentiation under normal conditions and after cytokine stimulation (in co-operation with projects B1, B3, B5, C1, C2; Platform Cell Biology (Gebhardt). We will assess the mechanisms explored for the size regulation of the liver suggested by simpler population models of cells with complex internal signaling networks (C2) within a model that considers the geometric and bio-mechanical constraints by the full lobule architecture. Vice versa, the assumption on the level of individual cells that are suited to explain the experimentally observed regeneration processes in a full lobule model provide hints and constraints for the function of the intracellular regulatory networks and signal pathways.