Active Digestion, Kidneys & Other Organs Lungs & Breathing

Investigating Genetic Mechanisms of Tissue Remodelling in the Inflamed Gut

Funder Wellcome Charity-funded
Recipient organisation University of Oxford
Funding £1.2M
Period Oct 2025 — Oct 2030

In plain English

AI plain-English summary

Inflammatory bowel disease twists the gut’s structural scaffolding, yet scientists do not understand how immune cells drive that damage. More than 240 genetic regions are linked to IBD, but the function of most remains unknown. This project focuses on one specific DNA variant on chromosome 22 that appears to alter how macrophages—immune cells involved in both inflammation and repair—produce PDGFB, a protein that activates fibroblasts and remodels tissue. The researcher has built a 3D human gut model that mimics the native extracellular matrix, allowing direct observation of how macrophages and fibroblasts interact in a realistic environment. Using patient-derived cells, gene editing, and high-resolution imaging, the work will trace the exact molecular pathways from genetic variant to tissue distortion. This is fundamental science. If successful, it will reveal a concrete mechanism linking a common genetic risk factor to gut scarring in IBD. That knowledge could eventually point to new drug targets for preventing tissue damage in chronic inflammation—not just in the gut, but potentially in other organs where fibrosis drives disease.

View original technical description
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.

View the original record at the funder ↗

Researchers

Laween Meran (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

From Genes to Disease: Investigating the Role Of ECM1 Variants in the Pathogenesis of Inflammatory Bowel Disease.
Training macrophages to resolve IBD
Determining the function of intestinal macrophage subsets in health, inflammation and repair
Laser capture microdissection to investigate bacterial handling defects in patients with monogenic inflammatory bowel disease
Genetic dissection of immunity and inflammation in a model of Crohn's colitis.

Original classification

Early-Career Award

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