A STUDY OF THE ROLE OF MICRORNAS IN INFLAMMATORY BOWEL DISEASE: THE EFFECT OF MIR-31 DYSREGULATION IN THE EXPRESSION OF TSLP IN ULCERATIVE COLITIS By Andrew Cia ridge Our current understanding suggests that Inflammatory Bowel Disease (lBD) is an immunological mediated disease triggered by unknown environmental factors in those who are genetically susceptible. MicroRNAs (miRNAs) are a class of small non coding RNAs that play a critical role in many immunological pathways by regulating gene expression. To date over 70 miRNAs have been identified as having a differential expression in IBD although their roles remain unlmown. Using microarray and RT-qPCR we have identified the differential expression of 7 miRNAs; miR-31, -146b, -194, -200b, -223, -375 and -422a, in the sigmoid mucosa of treatment na'ive Ulcerative Colitis. Of these, the expressions of miR-31 and -223 are also increased in mucosal Iymphocytes and the CD4+CD25in •• rm.dia •• subfamily. Using in silica analysis, thymic stromal Iymphopoietin (TSLP) is identified as a target for 4 of the 7 miRNAs; miR-31, -223, -194 and -422a. TSLP has been shown to be increased in TH2 mediated disorders of the lung and skin and implicated in epithelial barrier homeostasis and Iymphocyte function in response to luminal flora. Here we show for the first time the expression of TSLP by healthy Iymphocytes and a decreased expression in mucosal biopsies and mucosal Iymphocytes in active uc. In addition, using a human Iymphocyte cell model we demonstrate an increased expression of miR-31 in stimulated Iymphocytes which is inversely related to a decreased expression of TSLP mRNA and an even larger Abstract effect on the expression of TSLP protein in the same cells. Selective inhibition of miR-31 prevents the decrease in TSLP in stimulated Iymphocytes. The increased expression of miR-31 in UC actively decreases the expression of TSLP, a factor associated ' with epithelial homeostasis and less destructive inflammation. Manipulation of the miR-31 / TSLP pathway offers a potential therapeutic strategy for uc.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:588902 |
| Date | January 2013 |
| Creators | Claridge, Andrew |
| Contributors | Sanchez-Elsner, Tilman ; Fraser Cummings, J. R. ; Pender, Sylvia |
| Publisher | University of Southampton |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://eprints.soton.ac.uk/361257/ |
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