Investigating Genetic Mechanisms of Tissue Remodelling in the Inflamed Gut (360G-Wellcome-324115_Z_25_Z)

Distortion of tissue architecture is a frequent complication of chronic inflammation and a principal driver of organ dysfunction. This is exemplified in inflammatory bowel disease (IBD) where deformation of gut extracellular matrix (ECM) characterises refractory disease. However, the mechanisms by which immune cells interact with - and alter - the ECM remain poorly understood. Genetics provides a unique opportunity to discover disease mechanisms, but few of the >240 IBD risk loci are functionally resolved. Macrophages are dually involved in inflammation and tissue repair, making them key suspects for mediating immune effects on the ECM. I have identified IBD risk loci that appear to be involved in macrophage-fibroblast crosstalk, and will integrate functional genomics and tissue modelling to study disease mechanisms. To do this, I have engineered a 3D human gut model, facilitating the study of dynamic intercellular interactions within the native ECM. Using this, I will investigate an uncharacterised IBD-associated haplotype on ch22q13, which appears to modulate expression of PDGFB in macrophages – a gene encoding a potent stimulus for activated fibroblasts. Using patient-derived cells, I will study disease relevant aspects of macrophage biology within distinct spatial compartments of the gut, using gene editing and high resolution imaging to delineate the pathways involved.