Louie, Rikah;
(2020)
Investigating the role of IRF8 in atherosclerosis and ageing.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Atherosclerosis is the leading pathology underlying cardiovascular disease, with increasing prevalence amongst the aged population. This inflammatory, lipid-mediated disorder is caused by the accumulation of lipid-laden macrophages in the arterial vessels. Thus, reducing blood flow and ultimately leading to vessel occlusion. IRF8 is a haematopoietic transcription factor that is crucial for the development of myeloid cells and known to mediate their inflammatory responses. This thesis investigates the role of myeloid-IRF8 in atherosclerosis development and the mechanism underlying IRF8s involvement. This thesis also investigates transcriptional differences in myeloid-IRF8 expression amongst the healthy young and aged population to determine the potential of using IRF8 as a biomarker of ageing. Upon generating a novel myeloid-IRF8 deficient mouse model (M-IRF8KOLdlrKO), mice were challenged with a high fat western diet. Quantification of atherosclerotic lesions within the aortic root demonstrated M- IRF8KOLdlrKO mice developed significantly less plaque in comparison to WTLdlrKO controls. Thus, demonstrating myeloid-IRF8 reduction retards atherosclerosis development. Mechanistic studies, using RNA-sequencing, highlighted significant IRF8 regulation of genes involved in inflammation, chemotaxis and lipid metabolism. Therefore, contributing to IRF8-mediated differences in macrophage foam cell formation, cholesterol ester content and macrophage migration. This thesis also identifies IRF8-mediated differences in macrophage IFNb signalling in atherosclerosis. This has enhanced our understanding of the role of IFNb in atherosclerosis and how targeting IRF8 may alter macrophage response to IFNb in atherosclerosis. Taken together, this thesis has identified a novel role for myeloid-IRF8 reduction in atherosclerosis and enhanced our understanding of differences in the transcriptional regulation of IRF8 and its target genes in response to IFNb and in myeloid cells from the healthy aged population.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Investigating the role of IRF8 in atherosclerosis and ageing |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10098786 |
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