- Sigrid Juselius Foundation
80 000 euro
Proper regulation of inflammatory responses is important to avoid development of diseases such as chronic inflammation and cancer. To be able to control unwanted inflammation, flexible but precise mechanisms are required to tune inflammatory signals in the cells. The NF-ºB family of transcription factors are major mediators of inflammatory signalling. Post-translational modifications such as ubiquitination increase the possibilities to regulate protein functions, and we study how signalling mediated via ubiquitination regulates NF-ºB-dependent inflammatory signalling. We focus on ubiquitin signalling in intestinal and tracheal chronic inflammation and aim at identifying the regulators and the targets of ubiquitination, with the intention to find molecular switches that may be used to therapeutically target inflammatory signalling in chronic inflammation and cancer. In addition, we will study the role of ubiquitination in host-microbe interactions in the gut to understand how signalling between the microbiome and the intestinal epithelia is changes during chronic inflammatory conditions. As the signalling pathways regulating ubiquitination and NF-ºB activation, as well as the structure and function of the intestinal and tracheal epithelia are well conserved through evolution, we use the fruit fly Drosophila melanogaster as a model in our research. We have found both that ubiquitination is required for inflammatory NF-ºB responses in flies and that uncontrolled induction of ubiquitination drives NF-ºB-mediated inflammation in Drosophila. Here, we propose to study ubiquitin signalling in intestinal and tracheal epithelial homeostasis, with the aim to find means of controlling ubiquitin-regulated signalling events in chronic inflammation.