Mechanisms and consequences of neutrophil survival in hypoxia (360G-Wellcome-078244_Z_05_Z)

Neutrophils are important for innate immunity and are adapted to function at sites of inflammation which are relatively oxygen deplete. I have shown that physiological hypoxia (3 kPa O2) inhibits neutrophil apoptosis in vitro, a process directly regulated by the oxygen-sensitive transcription factor hypoxia inducible factor-1a (HIF-1a). HIF-1a is itself post-translationally regulated by a group of oxygen-sensitive enzymes, the prolyl hydroxylase domain containing enzymes (PHDs). 3 PHD isoforms are described and are expressed in neutrophils. In the presence of oxygen these enzymes hydroxylatethe HIF a subunit causing its rapid proteolytic destruction. I aim to elucidate the mechanisms regulating HIF-1a expression in neutrophils and determine the importance of these pathways for neutrophilic inflammation in vivo. My specific aims are to: i). Characterise PHD expression in neutrophils and effects on neutrophil function and apoptosis, comparing neutrophils from PHD1-3 deficient mice and mice with alteration of other HIF pathway componentsii). Examine consequences of PHD deficiency/HIF stabilisation in in vivo