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dc.contributor.advisorO'Sullivan, Jacintha
dc.contributor.advisorCreagh, Emma
dc.contributor.authorBARBER, GILLIAN LOUISE
dc.date.accessioned2020-06-24T08:04:13Z
dc.date.available2020-06-24T08:04:13Z
dc.date.issued2020en
dc.date.submitted2020
dc.identifier.citationBARBER, GILLIAN LOUISE, Inflammasome Involvement in Barrett's and Oesophageal Adenocarcinoma, Trinity College Dublin.School of Biochemistry & Immunology, 2020en
dc.identifier.otherYen
dc.identifier.urihttp://hdl.handle.net/2262/92830
dc.descriptionAPPROVEDen
dc.description.abstractBarrett's oesophagus is an inflammatory condition and a neoplastic precursor to oesophageal adenocarcinoma (OAC). Inflammasome signalling pathways contribute to acute and chronic inflammation, and can be enhanced by obesity. All inflammasome signalling results in caspase-1 activation, leading to the secretion of IL-1β and IL-18, and inflammatory cell death (pyroptosis). A full understanding of inflammasome involvement during Barrett's and OAC is yet to be achieved. However, increased IL-1β levels are reported in Barrett's, indicting a role for these pathways in disease progression. We hypothesized that inflammasome-mediated inflammation has an important role during oesophageal pathogenesis. Caspase-1 expression was profiled in three models of disease progression (Normal-Barrett's-OAC): a cell line model; a transgenic Barrett's mouse model; and resected tissue from Barrett's-associated OAC patients. In all three models, caspase-1 is shown to be highly upregulated during Barrett's (p<0.01), which is not maintained in later stages of disease. In the mouse model, results show that stromal caspase-1 correlates with histological scores for inflammation during disease progression (p<0.05). Similarly, the inflammasome component AIM2 is elevated during Barrett's, in vitro (p<0.05) and in the Barrett?s mouse model (p<0.01). Where epithelial (p<0.01) and stromal (p<0.05) scores correlate with disease progression. Ex vivo culture of Barrett's biopsies and Barrett's murine organoids in the presence of a caspase-1 inhibitor limits cytokine secretion, suggesting that targeting caspase-1 activity may represent a strategy for reducing inflammation. A high fat diet (HFD) and obesity are known risk factors for Barrett's and OAC. In this study we demonstrate involvement of the inflammasome pathway during associated inflammation. Inflammasome components are upregulated in response to OAC patient adipose conditioned media in an oesophageal cell line model, particularly in the normal cell line. To support this, we show that TLR2 (p<0.05), caspase-1 (p<0.05) and AIM2 (p<0.01) protein expression are elevated and IL-18 secretion (p<0.05) is reduced in normal murine oesophageal tissue from HFD-fed mice. Oesophageal AIM2 (p<0.05) and caspase-1 (p<0.05) expression levels are also upregulated in response to a high fat diet in Barrett's pL2-IL-1β mice. However, no differences are observed for TLR2 expression during a HFD. An additional finding of this study demonstrates that TLR2 activity mediates secretion of IL-8 orthologs, MIP-2 (p<0.001) and CXCL1 (p<0.01) in Barrett's organoids taken from the pL2-IL-1β mouse model. This signalling is inhibited using an inhibitor of TLR2 (p<0.001, p<0.05), suggesting a therapeutic advantage during Barrett's. Additionally, we observe TLR2 expression is upregulated in a Barrett's cell line (p<0.05), supporting previous preliminary studies implicating TLR2 and IL-8 during oesophageal disease. However, no differences in oesophageal TLR2 expression are observed during disease progression in the Barrett's mouse model when immunohistochemistry analysis is performed. Further studies are required to fully elucidate the role of TLR2 during oesophageal pathogenesis. Collectively, in this study we identify the inflammasome pathway and TLR2 signalling as potential mediators of inflammation during disease progression to Barrett's and OAC. Further, obesity enhances inflammation in oesophageal tissue, which may be further promoting disease. We speculate the therapeutic potential of targeting these pathways for prevention of oesophageal disease.en
dc.language.isoenen
dc.publisherTrinity College Dublin. School of Biochemistry & Immunology. Discipline of Biochemistryen
dc.rightsYen
dc.subjectImmunityen
dc.subjectInflammationen
dc.subjectObesityen
dc.subjectBarrett's esophagusen
dc.subjectInflammasomeen
dc.subjectEsophageal adenocarcinomaen
dc.subjectCaspase-1en
dc.subjectAIM2en
dc.subjectTLR2en
dc.titleInflammasome Involvement in Barrett's and Oesophageal Adenocarcinomaen
dc.typeThesisen
dc.contributor.sponsorJohn Scott Fellowshipen
dc.type.supercollectionthesis_dissertationsen
dc.type.supercollectionrefereed_publicationsen
dc.type.qualificationlevelDoctoralen
dc.identifier.peoplefinderurlhttps://tcdlocalportal.tcd.ie/pls/EnterApex/f?p=800:71:0::::P71_USERNAME:BARBERGen
dc.identifier.rssinternalid217518en
dc.rights.ecaccessrightsembargoedAccess
dc.date.ecembargoEndDate2025-06-23
dc.rights.EmbargoedAccessYen


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