Cells respond to inflammation-inducing stress by promoting the expression of factors required for survival and proliferation. Dysregulation of this mechanism and aberrant pro-inflammatory gene expression can lead to chronic inflammation. In the intestine, these inflammatory responses are regulated by NF-κB transcription factors and driven upstream of NF-κB by methionine 1-linked ubiquitin (Met1-Ub) chains, whose dysfunction is linked to diseases like cancer. However, it is unclear how NF-κB activation induces stimulus-dependent responses and how Met1-Ub contributes to this. The main aim of this project is to study the regulation of the Drosophila NF-κB Relish activation and target gene selection and how these regulate immune responses to various stimuli in the intestine in vivo. I will identify and analyze stimulation-dependent and inflammation-induced differences in Relish target genes, modifications, and binding partners and study their contribution to the fly intestinal immune responses. I will also study the use of Met1-Ub chains as a biomarker and investigate their role in intestinal Relish activation and target gene selection. The genomics, proteomics and imaging approaches used will provide insight into transcription factor target gene selection and the translation of cellular damage into specific inflammatory responses, and could lead to controlling unresolved inflammation and to the identification of biomarkers and drug targets for targeted therapies.

2024