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Endosignal

Final Report Summary - ENDOSIGNAL (Endosignal)

Crohn´s disease and ulcerative colitis are the two main forms of inflammatory bowel disease. In Europe 2.5-3 million people are affected by inflammatory bowel disease with several billion Euro of direct healthcare costs yearly. The objective of the project Endosignal was to investigate underlying molecular disease mechanisms. Previously, it had been demonstrated that the multi-domain protein FRMPD2 is a component of the immune host defence of gut derived epithelial cells. The epithelial immune host defence plays a critical role in inflammatory bowel disease. Because of the multi-domain nature of this protein it was suggested that it acts as a central scaffolding component of a larger protein complex. In the framework of the CIG Endosignal project we aimed to identify and characterise components of this protein complex. We succeeded in the identification of several potential candidates and were able to confirm physical interaction with some of them. In particular we focused on the interaction of FRMPD2 with a protein kinase regulated by the cell cytoskeleton. We could demonstrate that this kinase is involved in the regulation of the formation of epithelial cell-cell junctions. This is of particular interest as impaired epithelial barrier function is believed to contribute to inflammatory bowel disease. Furthermore, using cells with reduced expression levels of FRMPD2 or its associated kinase we were able to show that both proteins can modify the mechanical properties of cells, which resulted in modified migration behaviour. Thus the CIG Endosignal has allowed us to identify a novel signalling module with importance for epithelial barrier integrity, which is of potential relevance for the understanding of the disease mechanism of inflammatory bowel disease.
Within the Endosignal project we also aimed to analyse the role of FRMPD2 in the development of zebrafish with the goal to test the possibility whether zebrafish lacking functional FRMPD2 could serve as an in vivo model system for inflammatory bowel disease. We were able to demonstrate that FRMPD2 is expressed during zebrafish embryonic development and it appears to be down regulated in adult zebrafish. We generated a mutant zebrafish, which only expresses a truncated version of FRMPD2. This truncated version lacks more than three quarter of the full-length protein and lost its plasma membrane binding activity. Homozygous mutant frmpd2 fish did not show any obvious developmental defect, however a clear analysis of the results was complicated by additional mutations in the genetic background. The fact that we did not see any major effects of FRMPD2 on zebrafish development is encouraging that this zebrafish model could serve as an in vivo disease model in principle. However clearly, further experiments are needed in particular to generate a more homogenous genetic background of the mutant frmpd2 fish.
The CIG Endosignal has enabled the researcher to establish several important collaborations with academia and industry. The researcher is now collaborating with two Dutch companies to develop novel drug screening strategies for inflammatory bowel disease. The researcher could increase his group size now to five PhD students. Furthermore, the support provided by the CIG has tremendously helped to integrate the researcher in his current position, which is a permanent position currently at the level of a senior lecturer. The researcher is now member of several steering panels at the department including the research committee and the postgraduate affairs committee.
The researcher has also participated in a number of outreach activities aiming at the general public like “Discovery night” or “Krebs festival”. Here visitors (children and adults) were introduced to the overall aims of the Endosignal project and its potential socioeconomic impact. Furthermore, hands-on demonstrations using microscopic slides and live cell cultures were performed. Overall there was very positive feedback across the diverse lay audience. In summary the CIG Endosignal has been a perfect vehicle to integrate the researcher in his new department and formed the foundation for additional grant applications. The teams website is: https://www.sheffield.ac.uk/bms/research/erdmann