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Title: The role of microRNAS in Inflammatory Bowel Disease
Author: Whiteoak, Simon Richard
ISNI:       0000 0004 7656 2106
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2017
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Inflammatory bowel disease has complex and as yet not fully understood immune pathways. It is thought that inflammatory bowel disease develops in genetically predisposed individuals, with dysregulated immune responses to unknown environmental triggers. Manipulation of the immune pathways by biological monoclonal antibodies has not proved to be the panacea that it had been hoped for. MicroRNAs are single stranded RNA molecules which influence the translation of messenger RNA and hence protein synthesis. The altered expression of microRNAs in disease states in cancer and autoimmune diseases including inflammatory bowel disease is providing new insights into disease pathogenesis. This understanding has led to consideration of the utility of microRNAs in diagnostics, prognostics, and therapeutics in inflammatory bowel disease. As yet, research involving analysis of microRNA profiles in inflammatory bowel disease, has focussed on heterogeneous groups of patients. Studies have not taken in to account the therapy or disease severity of the subjects studied. Also, although there has been research looking at the dysregulated expression of microRNAs, the role individual microRNAs are playing in the disease and how they could be used therapeutically has not been explored. Using mucosal biopsies from patients on specific therapies, I performed RNA extraction and real time qPCR performed to analyse the profiles of microRNAs 31, 146a, and 155, and the target genes TNFα, SOCS1, and CCL18, in robustly phenotyped patients on conventional and biological therapies for ulcerative colitis, Crohn's colitis, and small bowel Crohn's disease. I then designed an ex vivo model to assess the effects of these therapies on microRNA and target gene expression, in treatment naïve tissue. I go on to investigate the specific interaction of microRNA 31, and Thymic Stromal Lymphopoetin (TSLP) in the dysregulated IL-13 pathway in ulcerative colitis. I do this by performing both microRNA 31 and TSLP mRNA expression by qPCR in samples from a clinical trial using anti-IL13 monoclonal antibody, and by measuring TLSP protein concentrations in mucosal biopsies by Enzyme Linked Immunosorbant Assay. I then investigate the direct targeting of TSLP by microRNA 31 by Dual Luciferase analysis. I show in this research that conventional and biological therapies have an important influence on the expression profiles of microRNAs and the target genes, and need to be taken into account when investigating microRNAs in inflammatory bowel disease. I also show that my ex vivo model can replicate the expression profiles seen in the treatment of inflammatory bowel disease, and could be utilised as a model for individualised medicine in the future. With this in mind, microRNAs are important in the immunoregulation of the bowel epithelium and are dysregulated in inflammatory bowel disease. MicroRNAs could possibly be utilised as diagnostic markers, predictive markers for response to treatment, or as future targets for novel therapies. I go on to show that increased microRNA 31 could predict response to a novel anti-IL13 monoclonal antibody, and hypothesise that this therapy could better be used as maintenance of remission therapy rather than as an induction agent. I also show that microRNA 31 is associated with decreased expression of TSLP mRNA and protein, in active moderate to severe ulcerative colitis. I show that by Dual Luciferase analysis microRNA 31 directly targets and inhibits TLSP. The microRNA 31/TSLP immune regulation in ulcerative colitis could be a target for future therapies.
Supervisor: Sanchez-Elsner, Tilman Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available