Professor of Renal Medicine
Cellular oxygen sensing: Oxygen is of fundamental importance for most living organisms. In higher animals such as humans appropriate delivery of oxygen (by the lungs, heart, blood, circulation and blood vessels) to all the cells is a considerable challenge - particularly as inadequate delivery will impair metabolism whereas excess oxygen is toxic. Not surprisingly, inappropriate oxygen delivery to cells plays a major role in many human diseases.
The group is analysing transcriptional responses to oxygen availability that regulate processes such as angiogenesis, cellular energy metabolism and proliferation/survival signals that operate in development. An important focus is on the hypoxia inducible factor (HIF) system that is regulated through oxygen dependent targeting of the transcription factor for ubiquitin mediated proteolysis. The group has demonstrated that this involves a novel method of protein recognition in which oxygen sensitive prolyl hydroxylation of HIF regulates ineraction with the von Hippel-Lindau tumour suppressor E3 ubiquitin ligase. Current lines of investigation include investigating the effects of mutations in components of this pathway both in vitro and in vivo, using molecular probes to examine the role of the HIF system in development, ischaemia/hypoxic disease, and tumour biology and investigating how this pleiotropic system can be manipulated for benefit in a variety of disease states.
Data fusion of vital signs: to address issues of patient deterioration during maintenance haemodialysis treatment we are developing novel ways to collect patient vital signs in real time during dialysis and analyse this data to provide early warning of impending deterioration. This work involves both using standard ways of measuring vital signs and developing novel approaches based on digital images.
Exercise in renal patients: I am part of a national consortium running an HTA funded project PrEscription of intraDialytic exercise to improve quAlity of Life (PEDAL Trial) and intend to run sub-studies looking at vital signs in dialysis patients before, during and after intra-dialytic exercise.
Genetics of renal disease:The group is pursuing genetic approaches to the understanding of renal disease, making use of whole genome sequencing.
Precisely Tuned Inhibition of HIF Prolyl Hydroxylases Is Key for Cardioprotection After Ischemia
Jatho A. et al, (2021), Circulation Research
Non-contact vital-sign monitoring of patients undergoing haemodialysis treatment.
Villarroel M. et al, (2020), Scientific reports, 10
Recent advances in the biology of tumour hypoxia with relevance to diagnostic practice and tissue-based research.
Macklin PS. et al, (2020), The Journal of pathology, 250, 593 - 611
Marked and rapid effects of pharmacological HIF-2α antagonism on hypoxic ventilatory control
Cheng X. et al, (2020), Journal of Clinical Investigation, 130, 2237 - 2251
Structure‐Activity Relationship and Crystallographic Studies on 4‐Hydroxypyrimidine HIF Prolyl Hydroxylase Domain Inhibitors
Holt‐Martyn JP. et al, (2020), ChemMedChem, 15, 270 - 273