Objectif Monocytes are central players in inflammation. Progress in understanding their differentiation in target tissues bears potential to manipulate their activities for therapeutic purposes. Here we propose to study the generation of intestinal macrophages (MΦs) as a paradigm, taking advantage of a unique experimental system to elucidate in vivo monocyte fates.The intestine hosts billions of bacteria that assist food uptake, but also pose a challenge, as we have to tolerate these beneficial commensals, yet rapidly mount immune responses to invading pathogens. Failure to maintain this balance causes inflammatory bowel disorders (IBD). Gut resident MΦs are key players in gut homeostasis and inflammation. Here we will study molecular parameters governing their generation from monocytes, as well as their interactions with the immediate tissue surrounding under pathological conditions. We focus on the molecular mechanisms leading to education of monocytes in small and large intestine using genome wide profiling of gene expression, chromatin state and transcription factor binding of monocytes and MΦs. Secondly, we will investigate epithelial and microflora-derived instructing cues, as well as sensory molecules on the MΦs that drive the education. Thirdly, we will study the impact of MΦs that fail to be trained and their role in the development of inflammation. Finally, we will use the insights gained to develop monocyte manipulation strategies that could aid the future development of IBD therapies.Our experimental system allows to follow the in vivo differentiation of engrafted monocytes, as physiological precursor cells, that acquire in a rapid synchronized development in the gut tissue physiologically relevant fates. Expected include (1) fundamental insight into the acquisition and maintenance of MΦ identities in a complex tissue context, (2) progress in our understanding of gut homeostasis and IBD, and (3) guiding insights for future monocyte-targeted therapy. Champ scientifique natural sciencesbiological sciencesmicrobiologybacteriologymedical and health sciencesbasic medicineimmunologynatural sciencesbiological sciencesgeneticsgenomesmedical and health sciencesbasic medicinephysiologyhomeostasis Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) ERC-AG-LS6 - ERC Advanced Grant - Immunity and infection Appel à propositions ERC-2013-ADG Voir d’autres projets de cet appel Régime de financement ERC-AG - ERC Advanced Grant Institution d’accueil WEIZMANN INSTITUTE OF SCIENCE Contribution de l’UE € 2 500 000,00 Adresse HERZL STREET 234 7610001 Rehovot Israël Voir sur la carte Type d’activité Higher or Secondary Education Establishments Chercheur principal Steffen Jung (Prof.) Contact administratif Gabi Brenstein (Ms.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée Bénéficiaires (1) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire WEIZMANN INSTITUTE OF SCIENCE Israël Contribution de l’UE € 2 500 000,00 Adresse HERZL STREET 234 7610001 Rehovot Voir sur la carte Type d’activité Higher or Secondary Education Establishments Chercheur principal Steffen Jung (Prof.) Contact administratif Gabi Brenstein (Ms.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée