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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:675475 |
| Date | January 2014 |
| Creators | Soundara Pandi, Sudha Priya |
| Publisher | Queen's University Belfast |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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