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MicroRNA Dynamics in an Ex Vivo Model of Multiple Sclerosis and the Impact of miR-155 in Remyelination
Multiple sclerosis is an autoimmune disease of the central nervous system that is widespread and represents a significant social and economic burden. Current therapeutics for the disease are largely ineffective at repairing the accumulating nervous system damage in progressive forms of the disease, and finding new interventions that can fulfil this role is a key goal of current research. Remyelination is the endogenous repair process that fails in patients with accumulating, unremitting symptoms, and microRNAs are increasingly appreciated to be key mediators in this process. However, many current models of remyelination are not well-characterized in terms of microRNA expression, and could be useful tools in examining pro-remyelination properties of microRNA-based interventions.
The aim of my PhD project was to characterize the microRNA expression dynamics in a widely-used ex vivo brain slice model of demyelination and remyelination, and to investigate the role of miR-155 in the repair process. In Chapter 3 I perform a global assessment of microRNA expression in the brain slice model over the course of demyelination and remyelination, and select key microRNAs for further analysis; namely miR-155, miR-21, miR-146a, miR-219 and miR-9. I demonstrate that several important microRNAs in remyelination show interesting expression dynamics in the brain slice model, and that the expression patterns of several predicted MS-related targets of these microRNAs are consistent with microRNA regulation; predominantly Arg2, Stat3, Lpp, Aff1 and Sh3b3. Furthermore, I carry out an assessment of the inflammatory profile of the brain slices through the course of the remyelination model. Chapter 4 brings the focus to a particular microRNA, miR-155, that is known to be a key mediator of inflammation. I show that global loss of this microRNA is associated with reduced inflammation but not improved remyelination in the brain slice model, pointing to a unpredicted role for this microRNA in the repair process. I further demonstrate that targeted, cell-specific loss of miR-155 in microglia does not potentiate remyelination. Finally in Chapter 5 I explore pharmacological interventions that suppress miR-155, and find that combined stimulation with lipopolysaccharide and interleukin 10 is associated with both enhanced remyelination and reduced inflammation, alongside miR-155 suppression. I further explore the 22 underpinnings of this treatment strategy and find that the mecahnisms of action may be mediated by the anti-inflammatory metabolic enzymes arginase 1 and arginase 2, the latter being a target of miR-155.
First SupervisorDr. Claire McCoy
CommentsSubmitted for the Award of Doctor of Philosophy to the Royal College of Surgeons in Ireland, 2022
Published CitationDuffy C,. MicroRNA Dynamics in an Ex Vivo Model of Multiple Sclerosis and the Impact of miR-155 in Remyelination [PhD Thesis] Dublin: Royal College of Surgeons in Ireland; 2022
- Doctor of Philosophy (PhD)
Date of award2022-06-01
- Doctor of Philosophy (PhD)
- Immunity, Infection and Inflammation