Wellcome Trust Clinical PhD Programme at the University of Oxford: 'Approaches to understanding regulatory pathways in atherosclerosis using genome-wide mapping of open chromatin with FAIRE-seq in foam cells. (360G-Wellcome-097089_Z_11_Z)

Approaches to understanding regulatory pathways in atherosclerosis using genome-wide mapping of open chromatin with FAIRE-seq in foam cells. Atherosclerotic vascular disease is the leading cause of morbidity and mortality worldwide. Atherosclerosis is an inflammatory condition and the lesions are packed with immune cells. A key pathogenic role is played by lipid loaded macrophages known as foam cells. The aim of this project is to improve our understanding of the pathophysiology of atherosclerosis to identify new therapeutic approaches. My approach is based on the genome-wide isolation and sequencing of regions of open chromatin in foam cells using FAIRE (formaldehyde-assisted isolation of regulatory elements) seq. Key goals 1. To generate FAIRE-seq data on foam cells, normal macrophages and other control cells. 2. To undertake bioinformatic analysis of this data to identify foam cell-specific regulatory DNA elements. 3. To undertake functional experiments to explore these findings a. At the whole genome level by examining the role of transcription factors or pathways suggested by similarities in foam cell- specific open chromatin regions across the genome. b. At the gene-specific level by examining the function of regulatory DNA elements identified in the MICA gene which encodes an immune ligand which promotes foam cell destruction and further inflammation in atherosclerosis. This project will provide training in a range of techniques involved in immunology, gene regulation, high throughput sequencing and bioinformatics.