Inflammatory bowel disease is a devastating disease affecting several million people in Europe. This proposal addresses the molecular mechanism of inflammatory bowel disease. The multi-PDZ domain protein FRMPD2 (FERM and PDZ domain containing protein 2) has been shown to be an integral part of the immune host defense of epithelial cells by recruiting NOD2 (Nucleotide-binding and oligomerization protein 2), a key player of the innate immune system, to the basolateral membrane in epithelial cells. In addition, FRMPD2 is involved in epithelial cell/cell adhesion regulating tight junction formation. Multi-PDZ domain proteins are scaffolding molecules assembling large protein complexes dedicated to signaling and membrane trafficking. Interaction of NOD2 with FRMPD2 places the NOD2 protein into a novel context being part of a larger protein complex. Using an interdisciplinary approach combining state of the art techniques from cell biology, protein chemistry, membrane physics and developmental genetics, this proposal aims at the identification and functional characterization of novel components of the FRMPD2 protein complex. In particular, this protein complex will be characterized with respect to mechanisms relevant to epithelial cell polarization and inflammatory bowel disease. Finally, the project aims to complement in vitro mechanistic and cell culture data with in vivo results by analyzing the role of the FRMPD2 complex in zebrafish development. Finally, using a Salmonella infection model, a zebrafish animal model for inflammatory bowel disease based on the FRMPD2 complex will be established. The results of this project will lead to a better molecular understanding of the disease opening potentially new avenues of treatments.