Scheme: Dorothy Hodgkin Fellowship
Organisation: University of Oxford
Dates: Oct 2010-May 2016
Summary: My group uses biochemical and biophysical methods to understand the molecular basis of oxygen-sensing enzymes, and to reveal ways in which they can be modulated. We are interested in oxygen sensors in animals and plants.
In humans and other animals, cells respond to decreased oxygen availability via a protein called HIF (Hypoxia-Inducible Factor) which triggers adaptations to increase oxygen delivery and improve metabolic efficiency. HIF plays roles in a number of diseases including cardiovascular disease and cancer, thus understanding and manipulating its regulation has a range of potential therapeutic benefits. HIF levels are regulated by oxygen-sensing enzymes called the HIF hydroxylases, maintaining low HIF levels under normal conditions. The HIF hydroxylases are highly efficient oxygen sensors; we are investigating the molecular features which enable them to react so sensitively to changing oxygen availability. Other enzymes in our cells which require oxygen include the histone demethylases which are involved in epigenetic regulation, governing which of our genes are turned on or off at any given time. We are investigating whether histone demethylases could also be sensitive to oxygen availability, and thus whether epigenetic regulation may be affected by hypoxic environments e.g. in ischaemic disease or solid tumours.
Hypoxia is also detrimental to plants, notably in flooded conditions. The plant response to this stress is via Ethylene Response Factors (ERFs), which direct the plant's ability to tolerate and recover from flooding. Oxygen-sensitive enzymes, the Plant Cysteine Oxidases, have recently been reported to regulate ERF levels, and we have characterised the chemical reactions that they catalyse. We are now investigating these enzymes in model and crop plant species to understand their structures and how they function with respect to oxygen. This will reveal ways in which their activity could be manipulated to improve flood tolerance in plants.