Supervisor(s): Professor Morag Young and Dr Alejandro Torres
Background
Virtually every aspect of cardiovascular physiology is regulated by the circadian clock. Disruption of circadian rhythms through ageing, obesity, poor sleep or shift work increases the risk of cardiovascular disease and metabolic dysfunction. Recent discoveries from our laboratory have identified the circadian clock as a previously unrecognised regulator of MR signalling. We have shown that MR activity varies according to biological time and that disruption of circadian pathways alters inflammatory, metabolic and fibrotic responses in the heart. These findings suggest that although circadian disruption is strongly associated with heart failure and cardiometabolic disease, the molecular mechanisms linking biological timing to MR signalling remain unknown. We also do not know whether restoring circadian organisation can improve therapeutic responses in heart failure.
Project summary
We hypothesise that circadian disruption reprograms MR signalling networks in the heart, promoting inflammation, fibrosis and metabolic dysfunction, and that restoration of biological rhythms can improve the efficacy of MR-targeted therapies.
Students will investigate interactions between circadian clock pathways and MR signalling using a combination of proteomic datasets and preclinical models of heart failure with preserved ejection fraction (HFpEF) and where available, serum samples from human cohort studies. Projects may include analysis of UK Biobank proteomic datasets, identification of blood biomarkers of circadian disruption, and mechanistic studies in mouse models of cardiometabolic disease. We have 2 cell types of interest — the cardiac cells and inflammatory cells. Projects exist for both.
Potential outcomes
The project will provide new insight into how biological timing influences cardiovascular disease and may establish a foundation for chronotherapy approaches in heart failure. Outcomes could include novel biomarkers of circadian disruption, improved patient stratification and new therapeutic strategies for high-risk populations such as shift workers.