Objective 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. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesbasic medicineimmunology Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) FP7-PEOPLE-2009-RG - Marie Curie Action: "Reintegration Grants" Call for proposal FP7-PEOPLE-2009-RG See other projects for this call Funding Scheme MC-IRG - International Re-integration Grants (IRG) Coordinator VIB VZW EU contribution € 75 000,00 Address SUZANNE TASSIERSTRAAT 1 9052 ZWIJNAARDE - GENT Belgium See on map Region Vlaams Gewest Prov. Oost-Vlaanderen Arr. Gent Activity type Research Organisations Administrative Contact Rik Audenaert (Mr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
