Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease in which remission requires mucosal healing, combining suppression of inflammation with restoration of epithelial barrier integrity. Advanced therapies have broadened treatment options, yet therapy choice remains largely empirical and no robust biomarkers exist to guide drug selection or monitor barrier repair. Mucins are key structural and regulatory components of the intestinal mucus barrier. Aberrant mucin expression is linked to disease activity and prognosis, and mucin genes show extensive RNA isoform diversity, but therapy-responsive mucin isoform signatures and their relationship to barrier function have not been defined at full-length resolution. This project combines single-nucleus long-read transcriptomics, multicentric longitudinal mucin isoform profiling, genomic mapping and patient-derived organoid (PDO) models to identify mucin isoform signatures associated with mucosal healing. Using Nanopore-based sequencing, we will resolve full-length mucin transcripts in UC biopsies, link isoform signature dynamics to clinical, endoscopic and histologic response, and assess in PDOs whether normalisation of aberrant mucin RNA isoforms parallels barrier recovery. By linking mechanistic insight into mucin biology with longitudinal clinical data, the project will provide a basis for future predictive biomarkers and for incorporating barrier-centred readouts into drug development and patient stratification in UC.
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