B2_NF-kB Pathway
Modelling of the NF-kB Dependent Apoptosis/Regeneration Switch in Hepatocytes
Pharmaceutical Biology and Biotechnology (University of Freiburg) Department for Gastroenterology (University Hospital of Düsseldorf) Life Imaging Center (University of Freiburg) Dr. Hans-Peter Fischer (PL), Dr. Thomas Hartsch (PhD), Dr. Julia Retey (PhD) Center for Data Analysis and Modelling (University of Freiburg) |
Project Summary: Regeneration of hepatocytes is a complex growth process being regulated by a coordinated network of different signal transduction pathways. In the initial phase of regeneration the cytokine TNF-a plays a key role activating the transcription factor NF-kB besides induction of other signalling cascades. Additionally, activation of NF-kB in hepatocytes further occurs in response to IL-1ß Whereas TNF-alpha and other cytokines, such as IL-6 are important for the initiation and propagation of liver regeneration, IL-1ß is a potent inhibitor of liver regeneration and hepatocyte proliferation. NF-kB activation represents a key event in IL-1ß signalling which does not only influence NF-kB target genes but also antagonizes signalling via the Jak/STAT cascade important for the signal-transduction of cytokines and growth factors such as IL-6. We therefore attempt to model the time and concentration dependent activation of NF-kB and its target genes in response to IL-1ß and its impact on STAT3 signalling and hepatocyte proliferation. NF-kB was shown to be crucially involved in the conversion of hepatocytes from proliferation into apoptosis after TNF-a stimulation, suggesting that NF-kB plays a pivotal role in the regulation of this switch. Therefore, our project aims to model TNF-alpha-induced NF-kB signal transduction in regenerating primary hepatocytes from B6 mice under standardized cell culture conditions with a special focus on the NF-kB dependent switch between survival, apoptosis and regeneration. To investigate this tempting subject, the target genes of the NF-kB transcription factor will be analysed in these different cellular stages with means of microarray analysis and single cell based expression measurement. Extensive data analysis will be accomplished to distinguish direct NF-kB target genes from secondary influenced cascade genes. Genome- wide promoter- analysis of target genes is expected to identify signatures for regeneration specific promoter sequences including other transcription factors binding sites. |
Former co-workers: Kilian Bartholomé, Claudia Kern, Simona Lang