Objective Asthma is a chronic inflammatory airway disease in which the transcription factor NF-kB plays a crucial role. NF-kB controls the activation of mast cells and dendritic cells (DC) that contribute to disease pathogenesis. Activation of NF-kB is tightly regulated by ubiquitination and deubiquitination of signaling intermediates. Studies in the host laboratory identified several deubiquitinating enzymes like A20 (also known as TNFaip3) and its binding partners to set the tone for NF-kB activation. A20 deficient mice succumb from an autoimmune inflammatory disease, through exaggerated responses induced by Toll like receptor (TLR) triggering, precluding a detailed analysis of the function of A20 in vivo. In the current proposal we will study the effect of cell-specific deletion of A20 on allergic airway inflammation, employing recently generated conditional A20 deficient animals, and crossing them with DC-specific and mast cell-specific deletor mice. In mast cells and DCs, we will study various ubiquitination and deubiquitination signaling events in the NF-kB pathway following activation with TLR agonists, cytokines and house dust mite allergen (HDM). Subsequently, the effects of cell-specific deletion of A20 on cellular function will be ascertained in vitro, using the most recent techniques in cell biology and cellular immunology. Next, we will study the effects of cell-specific deletion of A20 on the function of mast cells and DCs in vivo, focusing specifically on mast cell degranulation, passive cutaneous anaphylaxis, DC activation and parameters of T cell activation and differentiation. Finally, mast-cell or DC-specific A20 deficient mice will be subjected to asthma protocols driven by ovalbumin and HDM and salient features of asthma like eosinophilia, Th2 cytokine production and bronchial hyperreactivity will be studied. Upon completion of this project we will have a clear understanding of the regulatory role of A20 in the immune system and allergic disease. Fields of science medical and health sciencesclinical medicinepneumologyasthmanatural sciencesbiological sciencescell biologymedical and health sciencesbasic medicineimmunology Keywords A20 Allergology Chronic diseases NF-kB allergy dendritic cells mast cells ubiquitin 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) PEOPLE-2007-2-1.IEF - Marie Curie Action: "Intra-European Fellowships for Career Development" Call for proposal FP7-PEOPLE-IEF-2008 See other projects for this call Funding Scheme MC-IEF - Intra-European Fellowships (IEF) Coordinator VIB VZW Address Rijvisschestraat 120 9052 Zwijnaarde - gent Belgium See on map Activity type Research Organisations projects.administrative_contact Rik Audenaert (Mr.) Links Contact the organisation Opens in new window Website Opens in new window EU contribution € 218 525,77
