Wellcome Trust Clinical PhD Programme at the University of Oxford: The role of HIF prolyl hydroxylase enzymes in ventilatory acclimatisation to hypoxia (360G-Wellcome-099895_Z_12_Z)

Mechanisms underlying ventilatory acclimatization to sustained hypoxia are poorly understood, but could represent therapeutic targets for treatment of diseases characterized by hypoxaemia and breathlessness, including acute altitude sickness. The Ratcliffe laboratory specializes in the biology of Hypoxia Induced Factor (HIF), which co- ordinates the transcriptional response to hypoxia and is regulated by oxygen-dependent prolyl hydroxylase enzymes (PHD). Human and mouse studies show that genetic modifications of the PHD-VHL-HIF axis affect ventilation, although some results conflict. Experiments undertaken in Oxford show enhanced ventilatory responses to hypoxia in mice with PHD2 haplo-insufficiency. I will use genetic and pharmacological interventions along with ventilatory, morphological and electrophysiological phenotyping to establish whether the ventilatory effects seen in PHD2+/- mice are due to changes in cell number and/or intrinsic function. Further, I would test whether the ventilatory effects arise from cell autonomous processes in the type 1 cells and whether the phenotype is due to activation of Hif-1, Hif-2 or another substrate. If the effects are HIF-independent, I would seek novel components of the pathway controlling ventilatory acclimatisation to hypoxia. This project will allow me to address fundamental questions in physiology whilst providing me with training in many skills, including transgenic animal work.