Title:
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MicroRNA in retinal ageing and age-related retinal degeneration
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Ageing is the main risk factor for the sight threatening disease, age-related macular
degeneration (AMD) which causes central vision loss. Although the exact pathogenic
mechanism underlying this disease is not well known, recent advances in
understanding of how gene expression is regulated suggest a role for small nOI1-
coding regulatory RNAs called microRNAs. The main aims of this PhD project were
to characterise the endogenous microRNAs in retinal tissues and to investigate how
they change with age and in a model of AMD. In addition, how do specific
microRNAs regulate retinal pigment epithelium (RPE) function. Firstly, I
demonstrated that the small RNA population in three month-old C57BLl6J wild type
mice retina and RPE/choroid is extremely complex, including novel orthologs and
microRNAs, isomiRs, microRNAs synthesized via non-canonical via Drosha-independent
pathways and other small RNAs. Secondly, expression of these
microRNAs was changed with age. Half of the microRNAs expressed in
polycistronic clusters change with age in the same direction. MicroRNAs altered
with age were predicted to be targeting age-related pathways, retina specific
functions and inflammation-related pathways, especially TGF -β signalling. Thirdly,
miR-26a was highly expressed in RPE/choroid, down-regulated with age and was
involved in the regulation of TGF-β signalling. Inhibition of miR-26a caused a
change in YEGF expression, cell proliferation and migration . Finally, microRNAs
altered in the CCLT/-/ CX3CR 1 GrP/GFP animal model of geographic atrophy were
predicted to be targeting genes involved in pathways related to AMD pathology.
MicroRNAs altered at before an overt phenotype in this model animal also targeted
some of these pathways and may be a prelude to this disease pathology. Some of the
microRNA changed with age overlap with this animal model suggesting that
microRNA changes in retina contribute to .disease progression. Alhough miR-26a
expression changes in this model are not significant. Functional changes with miR-
26a inhibition suggest its potential as a future biomarker for ageing and a therapeutic
approach for age related macular degeneration. Thus, microRNAs playa major role
in ageing and age-related retinal degeneration.
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