"The project seeks to advance our knowledge of the innate immune system at two different but complementary levels, sensing and regulation of signalling. The first aim is centred on danger signals, and how they activate the immune system. We propose to use high-throughput RNA sequencing, molecular biology, fly and bacterial genetics to investigate the global network of genes and pathways that are involved in either endogenous (DNA and chromatin components) or exogenous (pathogen virulence factors) danger signal sensing. Drosophila is used here as a model system to analyse the complexities of host-pathogen interactions. As many bacteria use a common set of virulence factors to target different hosts, this work should lead to the identification of new defence genes and mechanisms in human. The second aim seeks to understand the mechanisms that fine-tune NF-ºB signalling in Drosophila and in mammals. NF-ºB mediates every aspect of inflammation and immune response through transcriptional programs that have to be orchestrated by yet unknown regulatory layers. The ability to effectively target inflammatory diseases for therapeutic intervention requires knowledge of the intricacies of these regulatory layers. First, we propose to characterize the molecular function of a new modulator of NF-ºB signalling that we have recently discovered, by using yeast two-hybrid screens, mass spectrometry and Drosophila genetics. In parallel, we propose to analyze the role of newly discovered and evolutionary conserved small RNAs in the regulation of the innate immune response in Drosophila. This exciting new area of research should lead to a better understanding of the control of immune reactions, one of the most important goals for medical research in the next decade."