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Using molecular genetic analysis of cardiovascular disease as a tool to define disease mechanisms and therapeutic targets.

Watkins

 

About the research

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 led to the idea that energy compromise is a key disease mechanism; clinical trials are underway to test new medical therapies based on this finding.  Our work on genetic causes of ‘sudden cardiac death’ syndromes has been translated into clinical practice through the Oxford BRC, leading to an NHS commissioned national DNA diagnostic service. This area of my work is integrally linked with the groups of Prof. Charles Redwood and Prof. Houman Ashrafian as we have worked closely together for many years.

I also 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.

A current 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, and our preliminary data indicate that this, and other aspects of remodelling, are mediated, at least in part, by cells of the immune system that accumulate in HCM myocardium. We have shown that ablation of the adaptive immune system markedly worsens remodelling in a well-validated HCM mouse model. 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 will test this by identifying the role of specific immune components in the progression of HCM using reductionist experiments in HCM mouse models, studies in affected human myocardium and large-scale human genetic interrogation. Identification of the immune activity involved will inform novel disease modifying therapy for established disease.

We also have active projects using human genetic approaches to define novel disease genes, and downstream mechanisms, in families with unexplained familial cardiac syndromes. This has been a productive source of insights into fundamental cardiac biology and also often leads to direct improvements in patient care.

Training Opportunities

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).

Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Publications

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.

Nelson, C. P., Goel, A., Butterworth, A. S., Kanoni, S., Webb, T. R., Marouli, E., . . . Watkins H, Deloukas, P. (2017). Association analyses based on false discovery rate implicate new loci for coronary artery disease. Nature Genetics, 49(9), 1385-1391. (H. Watkins corresponding author).

 

Supervisors