Project description DEENESFRITPL Colorectal cancer may result from too much of a good thing Tissue repair is regulated by a complex interplay among the immune system, injured tissue and microbiota. To make matters more complicated, inflammation can play a positive or a negative role. The molecular mechanisms underlying the interactions are largely unknown. Inflammatory bowel disease and colorectal cancer provide an opportunity to investigate the relationships among inflammation, immunity, microbiota, tissue repair and signalling pathways gone awry. The EU-funded project REpAIR is studying interleukin-22 (IL-22) and its inhibitor in these disease processes. IL-22, produced by immune cells, acts on intestinal epithelial cells to modulate microbiota composition and promote tissue regeneration. However, it can also promote chronic inflammation and cancer. Outcomes will shed light on how the same pathways can lead to either a physiological repair response or to disease and point to targeted therapies for immune-related diseases and cancer. Show the project objective Hide the project objective Objective Inflammation is fundamental to promote tissue regeneration upon injury, and in turn, the resolution of the immune response. Physiological tissue regeneration depends on fine-tuned interaction between the immune system, the tissue, and the microbiota. However, the complex communication between these three components and the molecules that mediate it are unclear. Understanding this is fundamental to prevent immune-mediated diseases and even cancer. This is particularly important at mucosal surfaces, where continued regeneration occurs. Therefore, we hypothesize that inflammatory bowel disease (IBD) and colorectal cancer (CRC) are a consequence of a miscommunication between these components. Interleukin-22 (IL-22) is one key orchestrator of this communication: It is produced by immune cells and by acting on intestinal epithelial cells, it modulates the composition of the microbiota and promotes tissue regeneration. However, IL-22 can also promote both chronic inflammation and cancer. Exactly what regulates these paradoxical effects remains unclear. Of note, there is an endogenous inhibitor of IL-22, namely IL-22 binding protein (IL-22BP), which blocks IL-22 activity. We hypothesize that a misguided spatio-temporal regulation of the IL-22 – IL-22BP axis is the cause of pathogenic effects of IL-22. In particular, we will analyse: (i) the location, and the functional and molecular heterogeneity; (ii) the origin and fate of IL-22 and IL-22BP producing immune cells; and (iii) the role of the microbiota in regulating them. To this end, we will use new transgenic and gnotobiotic mouse models, single cell RNA sequencing and human samples. In short, by studying the IL-22 - IL-22BP axis, we will understand how the complex interactions between the immune system, the tissue, and the microbiota lead to either physiological or pathological tissue regeneration. This will provide the basis for therapies controlling inflammation and tissue regeneration in a spatio-temporal manner. Fields of science medical and health sciencesclinical medicinegastroenterologyinflammatory bowel diseasenatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesbasic medicineimmunologymedical and health sciencesclinical medicineoncologycolorectal cancernatural sciencesbiological sciencesgeneticsRNA Keywords inflammatory bowel disease colorectal cancer T cells microbiota cytokines tissue regeneration Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2019-COG - ERC Consolidator Grant Call for proposal ERC-2019-COG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Coordinator UNIVERSITAETSKLINIKUM HAMBURG-EPPENDORF Net EU contribution € 1 356 125,00 Address Martinistrasse 52 20251 Hamburg Germany See on map Region Hamburg Hamburg Hamburg Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00 Beneficiaries (2) Sort alphabetically Sort by Net EU contribution Expand all Collapse all UNIVERSITAETSKLINIKUM HAMBURG-EPPENDORF Germany Net EU contribution € 1 356 125,00 Address Martinistrasse 52 20251 Hamburg See on map Region Hamburg Hamburg Hamburg Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00 HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH Germany Net EU contribution € 643 562,00 Address Inhoffenstrasse 7 38124 Braunschweig See on map Region Niedersachsen Braunschweig Braunschweig, Kreisfreie Stadt Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
