MRC DiMeN Doctoral Training Partnership: Biological mechanisms underlying the frailest of patients with peripheral artery disease

Peripheral artery disease (PAD) affects ~200 million people worldwide and alarmingly rates continue to increase. PAD is characterised by atherosclerotic blockages of arterial supply in the lower extremities and leads to debilitating muscle symptoms, however most treatments remain ineffective - partly because we do not fully understand the underlying biological mechanisms. Most PAD patients have multiple long-term conditions (e.g. diabetes, hypertension, dyslipidemia), are elderly, and develop sarcopenia (loss of muscle mass/function), which promotes severe frailty. In the clinic, vascular surgeons often face problems discharging patients with PAD due to severe frailty, which results in prolonged hospital stays, higher medical and social pressures, and further exacerbates the frailty syndrome. As such, a subgroup of the frailest PAD patients represent an urgent unmet clinical need faced by the NHS.  

It remains unknown what biological mechanisms underpin the frailest of patients with PAD, limiting effective therapeutic treatments being developed. In this project, therefore, you will explore whether the frailest PAD patients are characterised by a unique skeletal muscle signature that will allow novel biological mechanisms and therapeutic targets to be identified.  

To answer this, you will combine unique clinical and biological scientific approaches. First you will characterize frailty and sarcopenia phenotypes (muscle mass, strength, and physical function) alongside clinical outcomes (e.g. hospital stay, comorbidities) in a cohort of PAD patients to identify the frailest subgroup. Then, you will undergo extensive training to implement cutting-edge technology to quantify calf muscle biopsies of the frailest PAD patients, including assessing muscle structure (immunofluorescence, confocal/electron microscopy), function (muscle cell force measurements), metabolism (metabolomics via LC-MS; pPCR/Immunoblotting), and RNAseq to generate a ‘frailty transcriptome atlas’, to collectively identify novel biological mechanisms. Thereafter, further training will be provided enabling you to perform in vitro human muscle cell experiments allowing candidate therapeutic targets to be tested and subsequently validated in vivo using our unique preclinical models. This work will lay the foundation for future studies to translate your knowledge back to the clinic setting. 

You would be welcomed into a diverse, inclusive and dynamic environment, and provided with strong mentoring. Uniquely, you will support an exciting partnership linking muscle biologists with clinical vascular surgeons at the University of Leeds. Primary Supervisor Dr Scott Bowen (@LabBowen) has a strong track record in muscle biology (https://pubmed.ncbi.nlm.nih.gov/?term=Bowen+TS&sort=date; https://biologicalsciences.leeds.ac.uk/school-biomedical-sciences/staff/33/dr-scott-bowen) and translational science (1,2,3). Dr Patrick Coughlin (@coughlin_pa) is a Consultant vascular surgeon, treating PAD patients on a daily basis combined with clinical research (https://pubmed.ncbi.nlm.nih.gov/?term=Coughlin%20PA&sort=date&page=2; 4). Our team will take a unique translational ‘team science’ approach, combining clinical with fundamental biological expertise to provide an interdisciplinary and training experience. Our unique synergy will allow transition from the clinical to basic arena (and vice versa) in order to answer the project’s main aim, linking key areas related to frailty, ageing, and multimorbidity.   

Overall, this project will allow you to focus on a unique group of PAD patients, exploring some of the frailest, elderly, multi-morbid people in our society while receiving cutting-edge scientific training, in order to identify novel causes and treatments of a debilitating disease.  

Benefits of being in the DiMeN DTP: 

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of-the-art facilities to deliver high impact research. 

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors. 

Being funded by the MRC means you can access additional funding for research placements, training opportunities or internships in science policy, science communication and beyond. Further information on the programme and how to apply can be found on our website: 

https://www.dimen.org.uk/