The influence of HIF-prolyl hydroxylase-2 during colitis and inflammation-associated colorectal carcinogenesis in mice

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Inflammatory bowel disease (IBD) is a disorder with severe pathology and limited therapeutic options. Although the underlying causes of IBD remain largely undefined, the fundamental defect involves a loss of intestinal epithelial barrier function. Furthermore, IBD is a condition that also greatly increases the risk of colorectal cancer (CRC).Importantly, these inflamed and/or tumor sites are hypoxic relative to normal healthy tissue, and it has been shown before that this condition can be detrimental to the final outcome of the disease. Central players in these complex processes are the HIF prolyl hydroxylases (PHDs); oxygen sensors that have not only been shown to regulate hypoxia inducible factor (HIFs), but also interfere in the NFkB and TGFb pathway. Although it has been demonstrated that general PHD-inhibition can be protective in a mouse model of dextran sodium sulphate (DSS)-induced IBD, our preliminary data strongly suggest that mice deficient for PHD2 in different cell lineages are much more susceptible than their WT littermates.With this project we propose to unravel the cellular and molecular background of this sensitivity. Therefore, we will make use of our unique collection of different single and double conditional knock-out mice (PHD2/HIFas) that we developed during the Emmy Noether program or mice obtained through fruitful collaborations (EPO-Tg6). Next to HIF, as the main downstream mediator, we will also focus on the other aforementioned pathways using different in vivo and ex vivo approaches.In a model of chemically/inflammatory induced CRC (AOM/DSS), we were able to detect reduced tumor development in mice lacking PHD2 in their intestinal epithelial cells. The results of these initial experiments are in line with our earlier findings showing the pro-tumoral nature of the enzyme. The second line of this project will therefore be focused on the unraveling of the PHD2 effect during tumor initiation and propagation.Moreover, in view of the interdisciplinary research collaboration we plan to develop during the Heisenberg program (please see the Heisenberg application for details), we will also be able to use an impressive collection of samples from patients with ulcerative colitis and colitis-associated dysplasia and cancer. Thus, this will give us the opportunity to link our findings in the different mouse models to colon-related pathologies in humans.