Overall Graduate Prize Winner 2017
I studied medicine at Nottingham University and then moved to Oxford to complete post-graduate training in nephrology and internal medicine.
I obtained a Wellcome Trust Clinical Training Fellowship and undertook my DPhil Studies with Professor Chris O'Callaghan in the Nuffield Department of Medicine. My research focussed on the role of macrophages in atherosclerosis - the disease process by which fatty plaques accumulate in arteries.
In atherosclerotic plaques, macrophages take up lipids faster than they can effectively process the lipid and become foam cells. Atherosclerosis is recognised as a chronic inflammatory condition. Lipid-laden foam cells are harmful because they secrete pro-inflammatory mediators that recruit more inflammatory cells, release metalloproteinases that destabilize growing plaques and foam cell apoptosis releases further toxic lipids. A key goal of atherosclerosis research is to understand the molecular events governing foam cell formation so that one could intervene to reprogram macrophages or foam cells into a more helpful role and reverse atherosclerosis.
In my DPhil project, I studied the effects of atherogenic lipids on macrophage gene expression and the associated epigenetic changes in chromatin across the whole genome. My analysis provides a roadmap linking the external disease stimulus of atherogenic lipid to the regulation of genes within macrophages and the genetic variation that influences disease risk.
This work identified novel disease pathways, in particular we identified a role for the C/EBP beta transcription factor pathway in the macrophage response to atherogenic lipid. I also found mechanistic links between common genetic variants that influence coronary artery disease risk and epigenetic effects of lipids on macrophages. At one of these sites I discovered a mechanism by which variation at a single nucleotide alters atherogenic lipid-induced expression of an enzyme, PLPP3, involved in degrading pro-inflammatory mediators. Altering this pathway or the enzymatic activity of PLPP3 represents a new potential therapeutic avenue for atherosclerosis. I also studied the molecular mechanisms by which genetic variants influence gene expression in pancreatic islet cells and alter the risk of type 2 diabetes.
My current research involves using single cell transcriptomic and epigenomic analysis to probe the ecosystem of atherosclerotic plaques at cellular resolution and develop a new molecular classification of atherosclerosis.
Reschen, M. E., Lin, D., Chalisey, A., Soilleux, E. J. and O'Callaghan, C. A. (2016). "Genetic and environmental risk factors for atherosclerosis regulate transcription of phosphatase and actin regulating gene PHACTR1." Atherosclerosis 250: 95-105.
Reschen, M. E., Gaulton, K. J., Lin, D., Soilleux, E. J., Morris, A. J., Smyth, S. S. and O'Callaghan, C. A. (2015). "Lipid-induced epigenomic changes in human macrophages identify a coronary artery disease-associated variant that regulates PPAP2B Expression through Altered C/EBP-beta binding." PLoS Genet 11(4): e1005061.
Gaulton, K. J., Ferreira, T., Lee, Y., Raimondo, A., Magi, R., *Reschen, M. E., Mahajan, A., et al. (2015). "Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci." Nat Genet 47(12): 1415-1425. *Joint first author
Reschen, M.E, Kini, U., Hood, R. L., Boycott, K. M., Hurst, J. and O'Callaghan, C. A. (2012). "Floating-Harbor Syndrome and Polycystic Kidneys Associated With SRCAP Mutation." American Journal of Medical Genetics Part A 158A(12): 3196-3200.