MRC DTP in Precision Medicine

Identifying scar-associated macrophages in early Crohn’s disease

Supervisors

Dr Gareth Jones, School of Infection and Immunity, University of Glasgow
Dr Calum Bain, School of Infection and Immunity, University of Glasgow
Prof Prakash Ramachandran, Institute for Regeneration and Repair, University of Edinburgh

Summary

Crohn’s disease, with ulcerative colitis, form the principal inflammatory bowel diseases, which affect 1% of people in Edinburgh and Glasgow. These conditions cause remitting-relapsing bowel inflammation of unknown cause, which trigger diarrhoea, bleeding, abdominal pain and fatigue. These “flares” of disease over time, cause cumulative damage to the digestive tract, whereby chronic inflammation progresses to fibrosis or stricturing of the bowel, that is incurable and requires surgery to restore intestinal function.

We have shown intestinal macrophages are key orchestrators of both inflammation and repair, whose diverse roles can only be accomplished by the presence of multiple sub-populations of cells. We have identified a scar-associated macrophage (SAM) in advanced human disease and now seek to identify and profile the responsible initiating factors in early disease, leveraging a unique longitudinal -omics dataset. Here, patients have attended for intestinal sampling during active inflammation, and again 12months later. We have then identified those patients that have either “resolved” or “progressed” their disease to more advanced phenotypes.

This project will identify the niche specific cues and initiating cellular factors that result in SAM identity. Information from these multi-omic human datasets will then be validated in gene edited primary human macrophages to identify therapeutic targets for downstream manipulation.