Douglas Group - Functional coronary artery disease genetics - defining the function of new causal atherosclerosis genes

about the research

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. The aim of our laboratory is to identify novel genes involved in coronary artery disease which have the potential to be targeted by new therapeutic treatments. Our lab is highly collaborative working with world leading scientists such as Professor Keith Channon to achieve our aims. 

In this project you will use data from human genetic and multi-omics studies to identify novel coronary artery disease genes. Once candidate coronary artery disease genes have been identified, you will utilize data from local and international biobanks to investigate the role of candidate genes in coronary artery disease and other vascular diseases.  In vitro assays in primary human cells including vascular organoid models will then be used to understand their mechanism of action.  This project will utilize primary humans cells and iPSC derived vascular cells such as endothelial cells, vascular smooth muscle cells and monocytes. Gene editing techniques will be used to modify the expression of the gene of interest. Unbiased genomic and proteomic approaches will be utilized to interrogate the role of our gene of interest in cell biology. You will then have the option to use the information from these studies in a targeted fashion to investigate the role of the lead candidate gene in in vivo models of coronary artery disease, for example the PCSK9 model of atherosclerosis.  

This project gives the opportunity to use a broad range of computational, in vitro and in vivo techniques which can be tailored to the interest of the candidate.  A typical in vitro project would involve investigating the expression profile of the gene of interest in human tissue, e.g. arteries with or without atherosclerosis. You would then investigate how expression of the gene changes in primary human or iPSC derived endothelial cells, vascular smooth muscle cells and inflammatory cells in response to coronary artery disease stimulants. This would be followed by assessment of the consequences of changing the expression of the gene of interest in cells and organoid based models using genome editing techniques such CRISPR/Cas9 as on cell function and cellular signalling pathways.  

In a typical in vivo project along with some of the in vitro methods outlined above, the student will assess how loss or gain of function of the candidate gene alters cardiovascular function. We will evaluate physiological parameters such as blood pressure, 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.

Additional supervision will be provided by Professor Keith Channon and Professor Nicola Smart (DPAG).

training opportunities

This DPhil will be based in the World leading Division of Cardiovascular Medicine. This project will provide extensive opportunities to collaborate and network with other world leading scientist both within Oxford and in other World leading institutes.  The candidate will be expected to present their work at relevant National and International conferences. By the end of this project the candidate will have developed a wide range of transferable laboratory skills such as molecular biology techniques (protein and RNA analysis), cell culture techniques and In vivo models of cardiovascular disease. As well as numerous other transferable skills such as data analysis, scientific writing (through papers), presentation skills and public engagement.

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