Exploiting ES-62 to dissect dendritic cell d signals regulating initiation and the phenotype of the inflammatory response. (360G-Wellcome-083217_Z_07_A)

The core aim of the project is to dissect the signalling mechanisms underlying ES-62-mediated subversion of dendritic cell (DC) maturation to a phenotype that drives hyporesponsive/antiinflammatory T cell-mediated immune responses. Specifically, the major objectives of the project are 1. Define whether ES-62 subverts DC maturation by signalling via a TLR4/PAF-co-receptor complex 2. Identify key signals regulating the switch converting DCs from a pro- to anti-inflammatory phenotype 3. Define whether modulation of the DC signals targeted by ES-62 mimics the phenotype of immune responses associated with ES-62 in vivo By dissecting the molecular mechanisms underlying how ES-62 subverts DC maturation, we aim to identify candidate immunomodulatory targets to facilitate novel drug development for inflammatory disease. This project will be complemented by, and will achieve added value, in terms of reagents and training, by on-going projects identifying the molecular targets of the immunomodulatory actions of ES-62 in B cells and mast cells within our longstanding collaborative grouping (MM Harnett, AJ Melendez and W Harnett).