The Role of Protease-Activated Receptor-2 in Colonic Epithelial Wound Healing

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dc.contributor.advisorMacNaughton, Wallace Keith
dc.contributor.authorYatigalpoththe, Mahesha N. S.
dc.contributor.committeememberMcCafferty, Donna-Marie
dc.contributor.committeememberHirota, Simon Andrew
dc.contributor.committeemembervon der Weid, Pierre Yves
dc.date2019-11
dc.date.accessioned2019-07-03T13:44:36Z
dc.date.available2019-07-03T13:44:36Z
dc.date.issued2019-06-27
dc.description.abstractThe intestinal barrier function relies on the presence of a single layer of epithelial cells that selectively absorb nutrients and water while limiting intestinal content and gut microbiota into the lumen. When epithelial barrier function is compromised, unregulated translocation of microbiota and microbial products into the mucosa can result in intestinal inflammation as seen in IBD patients. Effective resolution of inflammation requires elimination of inflammatory triggers and this is partly dependant on epithelial wound healing. The intestine is constantly exposed to proteases originating from a variety of sources and these proteases can activate protease-activated receptors (PARs). The mechanism of intestinal epithelial wound healing is not completely understood, particularly in the context of proteases and PARs. It was recently shown that PAR2 activation transactivates epidermal growth factor receptor (EGFR) and also induces COX-2 expression in colonic epithelial cells. Based on this, it was hypothesized that PAR2-induced EGFR transactivation and COX-2 expression drive colonic epithelial wound healing. In the first part of the study, CMT-93 cells were characterized for PAR2 expression and PAR-2 induced COX-2 expression. PAR2 is primarily expressed in the plasma membrane with punctate immunoreactivity in the cytoplasm. Furthermore, the majority of PAR2 expression appeared to be basolateral. PAR2 activation by 2fLI (2-furoyl-LIGRLO-NH2) induced Ca2+ signaling. COX-2 expression was characterized using western blotting and PAR2 activation did not induce COX-2 expression in CMT93 cells. The effect of PAR2 activation in wound healing was investigated in the second part of the study. PAR2 activation induced wound healing and the treatment with the COX-2 selective inhibitor (NS-398) did not affect the PAR-2 induced wound healing, indicating that PAR-2 induced wound healing does not depend on COX-2 activity. The treatments with the EGFR tyrosine kinase inhibitor (PD153035), broad-spectrum matrix metalloproteases (MMP) inhibitor (GM6001) or Src tyrosine kinase inhibitor (PP2) inhibited PAR2-induced wound healing. These results suggest EGFR activity is required for PAR2-induced wound healing and PAR2 activation possibly transactivates EGFR via-matrix metalloproteinases and Src tyrosine kinase activity. In conclusion, this study shows the contribution of PAR-2 in epithelial wound healing, which could subsequently aid in the resolution of intestinal inflammation.en_US
dc.identifier.citationYatigalpoththe, M. N. S. (2019). The Role of Protease-Activated Receptor-2 in Colonic Epithelial Wound Healing (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/36688
dc.identifier.urihttp://hdl.handle.net/1880/110568
dc.language.isoengen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectProtease-activated receptorsen_US
dc.subjectColonic epitheliumen_US
dc.subjectWound healingen_US
dc.subjectInflammatory bowel disease (IBD)en_US
dc.subjectproteasesen_US
dc.subject.classificationBiology--Cellen_US
dc.subject.classificationPharmacologyen_US
dc.subject.classificationBiochemistryen_US
dc.titleThe Role of Protease-Activated Receptor-2 in Colonic Epithelial Wound Healingen_US
dc.typemaster thesisen_US
thesis.degree.disciplineMedicine – Gastrointestinal Sciencesen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameMaster of Science (MSc)en_US
ucalgary.item.requestcopytrueen_US
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