Research Report 2010 - MDC

Jana WolfStructure of the GroupGroup LeaderDr. Jana WolfScientistsDr. Antonio Politi*Graduate StudentsKatharina Baum*Uwe Benary*Bente KofahlMathematical Modelling ofCellular SystemsComplex diseases are often characterised by an accumulation of multiple perturbations inrather large and complex cellular networks. The consequences of these perturbations, suchas mutations or over-expression of proteins, can hardly be analysed by pure reasoning. Here,mathematical modelling contributes to a deeper understanding of the regulatory systems andprovides thus a better basis for the interpretation of high-throughput data and identification ofeffective drug targets.Our group develops and analyses mathematical models of signaling pathways and generegulatorynetworks in normal and disease states. For our investigations we use tools suchas simulations, bifurcation analyses and sensitivity analyses. These give insights into thedynamical properties of the systems and help to identify most sensitive processes and criticalregulations. Another important aspect is the investigation of cell specific differences insignaling and gene-regulatory networks since these are critically involved in the predictionof the efficiency and possible side-effects of drugs.Modelling of IKK/ NF-κB signalingBente KofahlIn this collaborative project with the group of ClausScheidereit at the MDC we aim for a systems levelunderstanding of the IKK/NF-κB signaling pathway.This pathway consists of a canonical and a non-canonicalbranch. Both have a distinct timing and distinct biologicalfunctions but are interconnected. On the onehand substrates and inducers of the non-canonicalbranch are produced in the canonical branch, on theother hand a control of the canonical part by the noncanonicalbranch was reported. We are interested in theregulation of the long-time behaviour of the pathwayand its malfunction in diseases, e.g. Hodgkin-lymphoma.In particular, we want to dissect the contributionof canonical and non-canonical modules underthese conditions. To that end we are investigating thekinetic properties, feedback regulations and interactingmodules of both signaling branches. In a first step wehave developed a mathematical model of the noncanonicalIKK/NF-κB pathway, which is currentlyrefined in an iterative cycle of experiments and modellingand extended towards canonical signaling.Wnt/ β-catenin signalingUwe Benary, Bente KofahlWnt/β-catenin signaling plays an important role indevelopment and tissue homeostasis. Its deregulationis associated with various diseases and cancer. We use amathematical model of the Wnt/β-catenin pathway tostudy the effect of β-catenin mutations criticallyinvolved in hepatocellular carcinoma. In collaborationwith Rolf Gebhardts group (Leipzig) we are interested inthe impact of the mutations on the dynamics of thesignaling pathway and the expression of target genesin hepatocytes.60 Cardiovascular and Metabolic Disease Research