Characterisation of the fibrotic microenvironment associated with strictures in patients with Crohn’s disease

Akiror, Sarah (2023). Characterisation of the fibrotic microenvironment associated with strictures in patients with Crohn’s disease. University of Birmingham. Ph.D.

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Abstract

Crohn’s disease is an inflammatory driven condition in which 50% of patients develop fibrostenosing strictures in the course of disease progression, this remains a clinical unmet need. The study aimed to characterise the molecular and cellular fibrotic microenvironment in fibrotic (stricture) vs non- fibrotic (proximal and distal) segments derived from resected tissue of CD patients. Bulk RNA and single cell sequencing was performed on stricture, proximal and distal segments. Biomarkers of interest were identified to include Gremlin 1, HDAC1 and FGF2 whose expression patterns were studies in relation to localisation of fibroblasts using multispectral imaging. Studies on the role on Gremlin 1 in regulation of the TGF-β/BMP signalling pathways were conducted. The readouts included fibroblast activation, proliferation and expression of extracellular matrix (ECM) related genes including \(\textit{COL1A1}\), \(\textit{ACTA2}\), \(\textit{FN1}\) and \(\textit{TIMP1}\). The data showed a distinct expression pattern associated with stricturing including upregulation of stromal cell linked genes, GREM1 expression was localised to the cell population identified as stromal cells. Knock down of \(\textit{GREM1}\) using siRNA showed a downregulation in expression of proliferation associated gene \(\textit{MKI67}\) and myofibroblast activation genes including \(\textit{ACTA2}\).

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):