'Regulation and dysregulation of immune cell signalling in the hypoxic inflammatory environment'. (360G-Wellcome-089384_Z_09_Z)

The oxygen tension in inflammatory sites, such as the synovium in rheumatoid arthritis, is very low. Our hypothesis is that this hypoxia perpetuates inflammation by promoting the production of reactive oxygen species (ROS) which damage proximal signalling molecules particularly protein tyrosine phosphatases (PTP), resulting in altered signalling and differentiation. Additionally, we will investigate how this process interacts with more established hypoxic pathways such as stabilisation of HIF-1?, to regulate the signalling and responses of immune cells in chronic inflammation. We will: 1. Investigate how hypoxia alters CD4 T lymphocyte signalling and differentiation with a particular emphasis on proximal signalling regulation by phosphatases. 2. Determine the effects of hypoxia on the differentiation and function of macrophages and dendritic cells and their ability to polarise T cell responses. 3. Determine the effects of hypoxia on the production and function of regulatory T cells. 4. Establish whether the function of the autoimmune-associated R620W variant of the PTP Lyp is affected by hypoxia-induced damage thus promoting dysfunction and loss of immune tolerance.