Objectif Programmed cell death is essential for homeostasis, and its deregulation contributes to human disease. Inflammasome-induced pyroptosis of infected macrophages contributes to host defense against infections, but the concomitant release of inflammatory danger signals and leaderless cytokines is detrimental in chronic inflammatory diseases. The central hypothesis of the PyroPop ERC Consolidator project is that inflammasomes are cytosolic platforms that couple pathogen sensing to multiple programmed cell death modes. This is based on our preliminary data showing that inflammasomes can be triggered to switch from inflammatory pyroptosis to programmed necrosis and non-inflammatory apoptosis. This suggests that the (patho)physiological outcomes of inflammasome activation may be modulated for therapeutic purposes. However, the molecular machinery and effector mechanisms of pyroptosis, inflammasome-induced apoptosis and programmed necrosis are virtually unknown. My objectives are (i) to explore the cleavage events and subcellular dynamics of pyroptosis by proteomics and high-resolution time-lapse microscopy; (ii) to clarify the molecular mechanisms of pyroptosis and inflammasome-controlled cell death switching; and (iii) to address how inflammasome-associated cell death modes impact on anti-bacterial host defense and chronic inflammatory pathology in vivo through the identification of pyroptosis-selective biomarkers and clinical analysis of pyroptosis-deficient mouse models. The central hypothesis in this regard is that inflammasome-mediated secretion of leaderless cytokines (such as IL-1β and IL-18) and danger signals may be mechanistically coupled to pyroptosis, but not apoptosis induction. By clarifying the mechanisms of inflammasome-controlled programmed cell death, this project may set the path for the development of an entirely novel class of inflammation-modulating therapies that are based on converting inflammatory pyroptosis into non-inflammatory apoptosis. Champ scientifique natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsmedical and health scienceshealth sciencesinflammatory diseasesnatural sciencesphysical sciencesopticsmicroscopymedical and health sciencesbasic medicinepathologymedical and health sciencesbasic medicinephysiologyhomeostasis Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Thème(s) ERC-CoG-2015 - ERC Consolidator Grant Appel à propositions ERC-2015-CoG Voir d’autres projets de cet appel Régime de financement ERC-COG - Consolidator Grant Institution d’accueil UNIVERSITEIT GENT Contribution nette de l'UE € 592 586,21 Adresse SINT PIETERSNIEUWSTRAAT 25 9000 Gent Belgique Voir sur la carte Région Vlaams Gewest Prov. Oost-Vlaanderen Arr. Gent Type d’activité Higher or Secondary Education Establishments Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 592 586,21 Bénéficiaires (3) Trier par ordre alphabétique Trier par contribution nette de l'UE Tout développer Tout réduire UNIVERSITEIT GENT Belgique Contribution nette de l'UE € 592 586,21 Adresse SINT PIETERSNIEUWSTRAAT 25 9000 Gent Voir sur la carte Région Vlaams Gewest Prov. Oost-Vlaanderen Arr. Gent Type d’activité Higher or Secondary Education Establishments Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 592 586,21 VIB VZW Participation terminée Belgique Contribution nette de l'UE € 676 229,16 Adresse SUZANNE TASSIERSTRAAT 1 9052 ZWIJNAARDE - GENT Voir sur la carte Région Vlaams Gewest Prov. Oost-Vlaanderen Arr. Gent Type d’activité Research Organisations Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 676 229,16 JANSSEN PHARMACEUTICA NV Belgique Contribution nette de l'UE € 729 099,63 Adresse TURNHOUTSEWEG 30 2340 Beerse Voir sur la carte Région Vlaams Gewest Prov. Antwerpen Arr. Turnhout Type d’activité Private for-profit entities (excluding Higher or Secondary Education Establishments) Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 729 099,63