Identification of the molecular pathways that mediate cytokine induced immunopathology of the gut epithelium

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dc.contributor.advisor Nally, Ken en Saini Rokade, Nisha 2021-09-27T13:20:18Z 2021-09-27T13:20:18Z 2020 2020
dc.identifier.citation Saini Rokade, N. 2020. Identification of the molecular pathways that mediate cytokine induced immunopathology of the gut epithelium. PhD Thesis, University College Cork. en
dc.identifier.endpage 334 en
dc.description.abstract Although the phenomenon of synergistic cell death induced by the combination of IFN-γ and TNF-α has been known for more than 30 years, the underlying mechanisms are still not clear. The main aim of my PhD was to identify the mechanisms which are required for the killing of human intestinal epithelial cells (Chapter-I) by this cytokine combination. A human kinome RNAi screen and a drug repurposing screen identified the Janus kinases (JAKs) JAK1 and JAK2 as the major kinases required for IFN-γ + TNF-α dependent synergistic cell death. While TNF receptor-1 (TNFR1) was also required, there was no direct dependency of cell death on TNFR1-downstream canonical apoptotic and necroptotic signalling pathways. Furthermore, we identified a non-canonical role for caspase-8 and receptor-interacting serine/threonine-protein kinase 3 (RIPK3) in the cell death signalling pathway (Chapter-II). For the first time we report that IFN-γ and IFN-γ + TNF-α induced JAK1/2-STAT1 signalling followed a dose-to-duration pattern of activation whereby increasing concentration of cytokines resulted in sustained JAK-STAT signalling leading to epithelial cell death. This dose-to-duration signalling pattern allowed cells to respond appropriately to increasing levels of inflammatory cytokines. RNA-sequencing revealed that sustained activation of the JAK1/2-STAT1 pathway resulted in the expression of a unique set of ‘late’ genes associated with different cell death pathways (Chapter-III). Phosphoproteomics identified potential target substrates for sustained JAK1 and JAK2 kinase activity. These JAK1/2 substrate proteins are associated with epithelial junctions, cell adhesion and cell-cell interactions, highlighting the importance of JAK1/2-STAT1 signalling in regulating the integrity of the epithelial barrier. Overall, our results identify the central underlying mechanisms underpinning IFN-γ + TNF-α induced cell death of intestinal epithelial cells and disruption of the intestinal epithelial barrier during intestinal inflammatory diseases. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2020, Nisha Saini Rokade. en
dc.rights.uri en
dc.subject Interferon gamma en
dc.subject Tumour necrosis factor alpha en
dc.subject Cytokines en
dc.subject Synergism en
dc.subject Cell death en
dc.subject Signalling en
dc.subject Dose-to-duration en
dc.subject Janus kinase en
dc.subject Organoids en
dc.subject RNA sequencing en
dc.title Identification of the molecular pathways that mediate cytokine induced immunopathology of the gut epithelium en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD - Doctor of Philosophy en
dc.internal.availability Full text not available en
dc.description.version Accepted Version en
dc.contributor.funder Science Foundation Ireland en
dc.description.status Not peer reviewed en Biochemistry and Cell Biology en
dc.internal.conferring Autumn 2021 en
dc.internal.ricu APC Microbiome Institute en
dc.relation.project info:eu-repo/grantAgreement/SFI/SFI Career Development Award/13/CDA/2171/IE/Identification of the Molecular Pathways that Mediate Cytokine Induced Immunopathology of the Gut Epithelium/ en
dc.availability.bitstream embargoed 2024-09-30

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© 2020, Nisha Saini Rokade. Except where otherwise noted, this item's license is described as © 2020, Nisha Saini Rokade.
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