Oxygen sensing and renal diseases
All metazoans have a powerful control system based on hypoxia-inducible factor (HIF), which regulates transcription in response to changes in oxygenation. This operates in the physiological range, shaping many aspects of cellular and organismal behaviour. It also contributes to a range of disease processes, most notably clear cell renal cell carcinoma (CCRCC), the most common form of kidney cancer. The HIF pathway is constitutively activated in the great majority of CCRCC through biallelic inactivation of the VHL gene; this is because VHL acts as part of a ubiquitin E3 ligase complex which specifically recognises HIF-α subunits that are hydroxylated at specific prolyl residues. The prolyl hydroxylation is carried out by prolyl hydroxylase domain (PHD) enzymes. Inhibitors of the PHD enzymes are now being tested in humans by several companies for treatment of anaemia and ischaemic conditions. Our main avenues of research at present are: identifying methods of targeting VHL defective cells; seeking to characterise a VHL-independent pathway of HIF regulation; interrogating the role of HIF activation in aspects of adaptive immunity; determining the effect of PHD inhibitors on prolyl hydroxylation events in proteins other than HIF-α; and investigating the role of altered cellular metabolism in inherited renal diseases.
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