Obiettivo Innate immune cells such as macrophages and dendritic cells produce potent inflammatory cytokines to mount an appropriate immune response against microbial threats. The related cytokines interleukin (IL)-1beta and IL-18 require cleavage by the cysteine protease caspase-1 to generate biologically active IL-1beta and IL-18. Caspase-1 itself is synthesized as zymogen that interacts with certain members of the intracellular NOD-like receptor (NLR) family in infected macrophages to form large protein complexes named ‘inflammasomes’. The importance of inflammasomes is evident from the genetic variations in the NLR proteins Nalp1 and Nalp3 that are associated with autoinflammatory disorders and increased susceptibility to microbial infection. However, the molecular mechanisms of inflammasome activation and the role of caspase-11 have remained unclear. Caspase-11 has been suggested as an upstream and downstream regulator of caspase-1 functions in LPS-stimulated cells. However, its role in specific infammasomes and its contribution to substrate cleavage in innate immunity remain to be explored. We generated caspase-11 knockout mice to characterize the physiological role of caspase-11 in inflammasome signaling and the innate immune response. In Aim 1, we will characterize the role of caspase-11 in activation of the different caspase-1 inflammasomes. In Aim 2, the proteome-wide caspase-11 degradome will be determined using mass spectrometry-based COFRADIC technology. Primary macrophages from caspase-11 knockout mice will be used to validate the caspase-11 degradome under activating conditions. These approaches will generate a wealth of new information regarding the role of caspase-11 in innate immunity. Elucidating the role of caspase-11 in inflammasome signaling and the innate immune response will provide new insights into the mechanisms governing immunity and may pave the way for new therapeutic approaches for autoimmune disorders. Campo scientifico natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesbasic medicineimmunology Programma(i) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Argomento(i) FP7-PEOPLE-2009-RG - Marie Curie Action: "Reintegration Grants" Invito a presentare proposte FP7-PEOPLE-2009-RG Vedi altri progetti per questo bando Meccanismo di finanziamento MC-IRG - International Re-integration Grants (IRG) Coordinatore VIB VZW Contributo UE € 75 000,00 Indirizzo SUZANNE TASSIERSTRAAT 1 9052 ZWIJNAARDE - GENT Belgio Mostra sulla mappa Regione Vlaams Gewest Prov. Oost-Vlaanderen Arr. Gent Tipo di attività Research Organisations Contatto amministrativo Rik Audenaert (Mr.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato