Investigation of the fundamental crosstalk between HIF-2a, HIF-1b and the NF-kB pathways in hypoxia and inflammation (360G-Wellcome-105307_Z_14_Z)

Recently several studies have demonstrated that hypoxia and inflammation are intimately linked, in particular at the molecular level. In fact, the crosstalk between the two main transcription factors involved in the pathways, Hypoxia Inducible Factors (HIFs) and NF-KB respectively, is extensive. To date the majority of research has focused on the regulation of HIF by NF-KB, whereas the contribution of HIF to the NF-KB pathway is still poorly understood. The Rocha laboratory already identified a role for HIF-1a in restricting the NF-KB pathway in mammalian cells and in Drosophila. However, other preliminary data suggested that, HIF-1 13, when over-expressed, can increase the NF-KB activity, and consequently the immune response in vivo in non-stimulated conditions. The aim of this project is to determine the regulatory role of HIF-113 in the control of the NF-KB pathway, and investigate the molecular interactions between the two factors. In addition, this project aims to elucidate how HIF-2a regulates the NF-KB pathway in hypoxia and inflammation. The biological significance of HIF-2a and/or HIF-1 13 regulation of the NF-KB pathway will be assessed using Drosophila me/anogaster as an in vivo model.