Investigating the Mechanism of Adherent-Invasive E. coli Induced Mitochondrial Fission in the Intestinal Epithelium
| dc.contributor.advisor | McKay, Derek Mark | |
| dc.contributor.author | Mancini, Nicole | |
| dc.contributor.committeemember | Shearer, Jane | |
| dc.contributor.committeemember | Shutt, Timothy E. | |
| dc.contributor.committeemember | Coombes, Brian K. | |
| dc.contributor.committeemember | DeVinney, Rebekah | |
| dc.date | 2019-11 | |
| dc.date.accessioned | 2019-05-14T21:48:39Z | |
| dc.date.available | 2019-05-14T21:48:39Z | |
| dc.date.issued | 2019-05-14 | |
| dc.description.abstract | Mitochondrial dynamics, a field which encompasses the processes of mitochondrial fusion and fission, was first described in 1914 by Lewis & Lewis. Since this original anecdotal depiction in chick embryos of mitochondria which formed extensive networks that dynamically and rapidly remodelled, the field has exploded to include reports of imbalanced mitochondrial dynamics in disease of almost any tissue in the body. Although many papers seek to understand the role of mitochondrial dynamics in inflammatory disease, the role for these processes in inflammatory bowel disease (IBD) has never been studied. My thesis seeks to provide preliminary data investigating this major gap in research of the role of mitochondrial dynamics in the gastrointestinal tract. Furthermore, recent studies have shown that imbalances in mitochondrial dynamics are common features of intracellular infection with a diverse array of microbial agents. As the etiology of IBD is heavily influenced by microbes in the gastrointestinal tract, my thesis studied the Crohn’s disease-associated pathobiont adherent-invasive Escherichia coli (AIEC), demonstrating the link between mitochondrial dynamics, host-microbe interactions, and potentially, IBD. Specifically, my thesis addressed the hypotheses that (1) AIEC drive mitochondrial fission in intestinal epithelial cells, and (2) AIEC-induced mitochondrial fission impacts intestinal epithelial function (e.g. cell viability, or barrier function). Infection by AIEC in intestinal epithelial cell lines induced massive mitochondrial fragmentation, which was associated with mitochondrial dysfunction. The mechanism of AIEC-induced mitochondrial fragmentation involved invasion of bacteria, and the host fission protein Drp1 (dynamin-related protein 1). Downstream of mitochondrial fission, apoptosis, loss of barrier function, and transcription of interleukin-8 occurred. Treatment with the Drp1 inhibitor Mdivi1 blocked the loss of barrier function that occurred in association with AIEC infection. This mechanistic work has laid the foundation to explore the role of AIEC-induced mitochondrial fission in the function of the gastrointestinal epithelium. Preliminary data showed an imbalance in mitochondrial dynamics mediators by mRNA and protein expression in IBD patients and in murine models of colitis, demonstrating a link between mitochondrial dynamics and IBD for the first time, setting the stage for future studies thoroughly investigating the role for mitochondrial fission and fusion in the etiology of IBD. | en_US |
| dc.identifier.citation | Mancini, N. (2019). Investigating the Mechanism of Adherent-Invasive E. coli Induced Mitochondrial Fission in the Intestinal Epithelium (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. | en_US |
| dc.identifier.doi | http://dx.doi.org/10.11575/PRISM/36517 | |
| dc.identifier.uri | http://hdl.handle.net/1880/110345 | |
| dc.language.iso | eng | en_US |
| dc.publisher.faculty | Cumming School of Medicine | en_US |
| dc.publisher.institution | University of Calgary | en |
| dc.rights | University 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.subject | Gastrointestinal Science | en_US |
| dc.subject.classification | Biology--Cell | en_US |
| dc.subject.classification | Microbiology | en_US |
| dc.subject.classification | Biology--Molecular | en_US |
| dc.title | Investigating the Mechanism of Adherent-Invasive E. coli Induced Mitochondrial Fission in the Intestinal Epithelium | en_US |
| dc.type | doctoral thesis | en_US |
| thesis.degree.discipline | Medicine – Gastrointestinal Sciences | en_US |
| thesis.degree.grantor | University of Calgary | en_US |
| thesis.degree.name | Doctor of Philosophy (PhD) | en_US |
| ucalgary.item.requestcopy | true |