Downstream NF-kB signaling pathways activated by inflammatory stimuli, the NF-kB transcription factors play a central role. They are responsible for hundreds of gene activation pro- or anti-inflammatory activity. They are responsible for hundreds of gene activation pro- or anti-inflammatory activity. Using Drosophila as a model, our team recently isolated a new member of the IMD pathway, called Akirine. This protein, which is conserved among metazoans, is necessary for NF-kB signaling. Its action is quite original because our work has shown that the Akirine acts as a selector able to influence the choice of target genes of NF-kB to transcribe, in insects as in mammals. The Akirines allow the NF-kB factor preferentially target genes in pro-inflammatory activity and not the genes involved in the resolution of inflammation. This type of strobe molecules represents the “missing link” to i) our understanding of the complexity and selectivity of the NF-kB signaling and ii) the development of the new generation of anti-inflammatory molecule. In this context our group primarily develops three projects:
I / Epigenetic control study of the inflammatory response
Our research shows that the Akirine is in the regulation of NF-kB signaling pathways via the recruitment of complex chromatin remodeling SWI / SNF, and the filing of specific epigenetic marks on the promoters of NF-kB target genes and dependency on Akirine. We propose to identify in Drosophila and human cell lines and murine, epigenetic mechanisms involved in the control of the transcriptional selectivity of target genes of NF-kB.
II/ Role of noncoding RNA in the regulation of the NF-kB pathway in Drosophila
As part of LabexNetRNA (http://labex-ibmc.u-strasbg.fr/NetRNA/) we aim to understand the role of non-coding RNAs in transcriptional regulation and selectivity of the innate immune response in Drosophila.
III/ Activation of the immune response by danger signals
Metazoan innate immune response can be activated by microbial patterns or by “danger signals” as microbial protease activities. We use Drosophila and specifically the NF-kB pathway “Toll” to identify the NF-kB signaling downstream of these danger signals which is still poorly understood.
Furthermore, we develop a screening strategy to identify small pharmaceutical molecules able to interfere with the inflammatory response.