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Functional coronary artery disease genetics - defining the function of new causal atherosclerosis genes from CAD GWAS loci using in vitro and in vivo models


   Radcliffe Department of Medicine

   Friday, December 03, 2021  Competition Funded PhD Project (Students Worldwide)

Oxford United Kingdom Cardiology Cell Biology Genetics Molecular Biology

About the Project

Despite significant advancements in its treatment coronary artery disease is the leading cause of death in both the UK and world-wide, accounting for over 66,000 deaths in the UK each year. Genome wide association studies have enabled us to identify genes which are associated with cardiovascular disease at the level of the whole genome. These novel genes, which are not associated with traditional risk factors, have the potential to identify novel treatment strategies for coronary artery disease. However, the challenge now is to establish the role of these genes in the pathology of cardiovascular disease. The work in my lab aims to establish the role of novel candidate genes in cardiovascular disease.

Working in close collaboration with bioinformaticians we identify novel candidate genes from GWAS implicated loci. Once candidate genes have been identified we use targeted cardiovascular disease relevant in vitro cell based assays in primary human cells to understand how the candidate gene impacts and cell function. Proteomic and genomic analysis is used to give an unbiased analysis of candidate gene function. This is complimented by advanced cellular imaging as well as molecular biology techniques. 

The information gained from these In vitro studies is then used in a targeted fashion to investigate the role of the candidate gene in models of In vivo cardiovascular disease, in particular the development and regression of atherosclerosis and models of altered vascular function such as vascular injury and ischaemia models. We also utilize data from local and international biobanks to investigate the role of candidate genes in vascular biology.

Doctoral students have the flexibility to focus either on in vitro cell based assays or in vivo models of cardiovascular disease. A typically In vitro project would involve investigating the expression profile gene of interest in human tissue (e.g. arteries with or without atherosclerosis and cells (e.g endothelial cells, vascular smooth muscle cells and inflammatory cells) implicated in coronary artery disease. This would be followed by assessment of the consequences of loss or gain or function of the gene on cell function.  It is not anticipated that within the time of the project that detailed in vivo analysis of the gene of interest would be achievable. However, if the student was interested there maybe the scope to extend this project to in vivo studies. In a typically in vivo project, the student will assess the how loss or gain of function of the candidate gene alters vascular function. We will evaluate physiological parameters such as blood pressure and contractile and dilator function of blood vessels before going on to investigate the role of the candidate gene in vascular pathology using models of atherosclerosis and vascular disease.

This DPhil will be based in the Division of Cardiovascular Medicine at the Welcome Centre for Human Genetics. We are part of a wider scientific community with expertise in Cardiovascular Disease allowing for collaborative work with other senior scientist. By the end of this project the candidate will have developed a wide range of laboratory skills such as molecular biology techniques (protein and RNA analysis), cell culture techniques and In vivo models of cardiovascular disease. Training in scientific techniques as well as scientific presentation and writing will be given throughout the project.

Additional supervision will be provided by Professor Keith Channon and Professor Marc Crabtree..

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.


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 fees paid and will receive a stipend of £18,000 per annum.

For October 2022 entry, the application deadline is 3rd December 2021 at 12 noon midday, UK time.

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


References

1 Douglas G, Mehat V, Al Haj Zen A, Akoumianak I, Goel A, Rashvrook VS, Trelfa L, Donovan L, Drydale E, Chuaiphichai S, Antoniades C, Watkins H, Kyriakou T, Tzima E, Channon KM. A key role for the novel coronary artery disease gene JCAD in atherosclerosis via shear stress mechanotransduction. Cardiovascular Research, doi:10.1093/cvr/cvz263. 2019
2 Endothelial Cell Tetrahydrobiopterin Modulates Sensitivity to Ang (Angiotensin) II-Induced Vascular Remodeling, Blood Pressure, and Abdominal Aortic Aneurysm. Chuaiphichai S. et al, (2018), Hypertension, 72, 128 - 138
3 Roles for endothelial cell and macrophage Gch1 and tetrahydrobiopterin in atherosclerosis progression. Douglas G. et al, (2018), Cardiovasc Res, 114, 1385 - 1399
4 JCAD, a Gene at the 10p11 Coronary Artery Disease Locus, Regulates Hippo Signaling in Endothelial Cells. Jones PD. et al, (2018), Arterioscler Thromb Vasc Biol, 38, 1711 - 1722
5 A key role for tetrahydrobiopterin-dependent endothelial NOS regulation in resistance arteries: studies in endothelial cell tetrahydrobiopterin-deficient mice. Chuaiphichai S. et al, (2017), Br J Pharmacol, 174, 657 - 671
6 Effect of irradiation and bone marrow transplantation on angiotensin II-induced aortic inflammation in ApoE knockout mice. Patel J. et al, (2018), Atherosclerosis, 276, 74 - 82

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