Coventry University Featured PhD Programmes
University of Warwick Featured PhD Programmes
University of Reading Featured PhD Programmes

Genetics of inherited cardiovascular disease


Radcliffe Department of Medicine

This project is no longer listed on FindAPhD.com and may not be available.

Click here to search FindAPhD.com for PhD studentship opportunities
Prof H Watkins , Prof H Ashrafian , Prof C Redwood No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

My group uses molecular genetic analysis of cardiovascular disease as a tool to define disease mechanisms and therapeutic targets. We work on rare/Mendelian genetic diseases, as well as common complex traits, and are currently also interested in the interface – the influence of common variants on outcome in rare disease.

In rare disease genetics, I have had a longstanding focus on inherited heart muscle diseases, in particular hypertrophic cardiomyopathy, which is a relatively common Mendelian condition which puts affected individuals at risk of sudden cardiac death. My group’s work, using molecular biological, model organism and clinical research approaches, has defined underlying disease mechanisms and treatment targets. Our work on genetic diagnosis of cardiomyopathy and other ‘sudden cardiac death’ syndromes has changed practice worldwide. My cardiomyopathy work is integrally linked with the groups of Prof. Charles Redwood and Prof. Houman Ashrafian as we have worked closely together for many years.

One current area of focus is in laying the groundwork for nucleic acid therapies that have the potential to cure inherited cardiomyopathies – through gene silencing, replacement or editing. To evaluate this we are modelling the effects of cardiomyopathy mutations in myofilament protein genes, and potential interventions, in iPSC-derived cardiomyocytes. The iPSC-cardiomyocyte work is led by Dr Chris Toepfer, a Henry Wellcome Fellow who brings biophysical expertise to the wider group.

A related area of focus is exploring the basis of cardiac remodelling in hypertrophic cardiomyopathy, in particular the role of the immune system. We have shown that there is metabolic crosstalk between stressed cardiomyocytes and neighbouring cells, mediated, at least in part, by cells of the immune system that accumulate in HCM myocardium. We hypothesise that local cardiac immune activity, both acquired and innate, plays an essential and dynamic role in HCM with, as is typical in immunity, a balance of deleterious and protective effects. We are testing this in mouse models.

In common disease genetics, I lead a research group investigating susceptibility genes for coronary artery disease, now the main cause of premature mortality worldwide, working closely with Prof. Martin Farrall who leads on statistical genetic approaches. This work is now entering an exciting phase where we can use functional genomic tools to understand new biology. We have a particular interest in genetically implicated processes in the vessel wall and pursue this in collaboration with Prof. Keith Channon, Dr. Gillian Douglas and Prof. Ellie Tzima and with a network of collaborators funded by a BHF:DZHK award.

Our genetic discovery efforts have included recent large scale GWAS in hypertrophic cardiomyopathy (in press in Nature Genetics) which have revealed surprisingly large influences of common variants on disease risk. We are now examining the utility of polygenic risk scores for risk prediction as well as the underlying biological implications of the many new loci. We also have active projects using human genetic approaches to define novel disease genes (eg through the 100k genomes project), and downstream mechanisms, in families with unexplained familial cardiac syndromes. This continues to be a productive source of insights into fundamental cardiac biology and also often leads to direct improvements in patient care.

Depending on the prior experience of the successful candidate, projects in the group would provide training in human genetic analysis, including gene discovery through whole genome sequencing, creation and analysis of mouse models and/or human iPSC-derived cardiomyocytes (both via genome-editing with CRISPR-cas9), cardiac phenotyping of mouse and cellular models. The immunology project will employ cutting edge approaches for investigating immune cell subsets, including single cell genomic analysis, well-established in vivo mouse models, advanced immunological and imaging techniques (e.g. FACSymphony, cell sorting, CyTOF, two-photon confocal fluorescence microscopy, and light sheet microscopy).

Additional supervision may be provided by Dr Chris Toepfer.

More information about training opportunities can be found on our website.

Funding Notes

Funding for this project is available to scientists through the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.

For October 2021 entry, the application deadline is 8th January 2021 at 12 noon (midday).

Please visit our website for more information on how to apply.

References

Watkins H, Ashrafian, Redwood C. Mechanisms of Disease: Inherited Cardiomyopathies. New Engl J Med 2011; 364:1643-56.

Ashrafian H, Czibik G, Bellahcene M, Aksentijević D, Smith AC, Mitchell SJ, Dodd MS, Kirwan J, Byrne JJ, Ludwig C, Isackson H, Yavari A, Støttrup NB, Contractor H, Cahill TJ, Sahgal N, Ball DR, Birkler RI, Hargreaves I, Tennant DA, Land J, Lygate CA, Johannsen M, Kharbanda RK, Neubauer S, Redwood C, de Cabo R, Ahmet I, Talan M, Günther UL, Robinson AJ, Viant MR, Pollard PJ, Tyler DJ, Watkins H. Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway. Cell Metabolism. 2012 Mar 7;15(3):361-71.


Yavari, A., Bellahcene, M., Bucchi, A., Sirenko, S., Pinter, K., Herring, N., . . . Watkins H, Ashrafian, H. (2017). Mammalian γ2 AMPK regulates intrinsic heart rate. Nature Communications, 8(1), 1258.

Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, Exome Aggregation Consortium, MacArthur DG, Farrall M, Cook SA, Watkins H. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2016 Aug 17. doi: 10.1038/gim.2016.90.

Toepfer CN, Wakimoto H, Garfinkel A, McDonough B, Liao D, Jiang J, Tai AC, Gorham JM, Lunde IG, Lun M, Lynch TL 4th, McNamara JW, Sadayappan S, Redwood CS, Watkins H, Seidman JG, Seidman CE. Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin. Sci Transl Med. 2019 Jan 23;11(476). pii: eaat1199. doi: 10.1126/scitranslmed.aat1199.

Harper A et al. “Common genetic variants, and modifiable risk factors, underpin susceptibility
and expressivity in hypertrophic cardiomyopathy”. Nature Genetics in press.


FindAPhD. Copyright 2005-2021
All rights reserved.