Investigation of the tissue specific role for IKK beta in inflammation and immunity. (360G-Wellcome-081093_Z_06_Z)

Nuclear Factor (NF)-kB is a ubiquitous transcription factor with important roles in inflammation and immunity. My previous research has suggested a role for NF-kB in the resolution of inflammation in vivo (Nat Med 7:1291-7 2001). This project is centred on my discovery of a tissue specific role for NF-kB in inflammation, revealed by Cre/lox mediated gene targeting of IkB kinase (IKK) ß in lung epithelial cells and myeloid cells, presented as preliminary data in the proposal. These experiments uncovered a new function for IKKß in suppression of the 'classically' activated macrophage phenotype. The research proposed will further establish the hypothesis that NF-kB plays a tissue specific role in inflammation by generating new transgenic mouse lines and extending the in vivo analysis to models of both acute and chronic inflammation. Further in vitro studies will characterise the role of IKKß in the regulation of macrophage function and activation and define the molecular mechanism for the suppression of macrophage activation by IKKß. The key goals of this proposal are:Characterise the role of IKKß and NF-kB in the suppression of inflammatory macrophage activation.Determine the specific roles of IKKß in fibroblasts and macrophages in acute inflammation and antigen-driven chronic inflammation.