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Title: Proinflammatory signalling by receptor for advanced glycation end products (RAGE), an important mediator of retinal pigment epithelium (RPE) dysfunction and age related macular degeneration (AMD)
Author: Dasari, Shilpa
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2013
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AGEs accumulate in the Bruch's membrane with a detrimental effect on RPE function with age. Receptor for AGEs (RAGE) is hypothesised to have an important role in RPE dysfunction and AMD pathogenesis. It is reported to be highly expressed in the RPE and its activation leads to the induction of pro-inflammatory cytokines and oxidative stress in many other tissues. SI OOB is a ligand for RAGE and its role in retinal inflammation is not clear. This project investigated the link between RAGE activation by S100B and how this relates to RPE dysfunction and the pathogenesis of AMD. Serum analysis using ELISA showed that S100B was significantly elevated in nvAMD with no significant changes in sRAGE levels. Laser induced CNV in RAGE -/- and WT mice showed that the genetic depletion of RAGE results in smaller lesion size and concomitant infiltration of macrophages into the sub-retinal space. RAGE knock-down in endothelial cells (HMEC-l) was achieved by siRNA and SI OOB treatment almost abolished VEGF secretion and angiogenesis in RAGE knockdown cells compared to control cells which was measured by migration and tube formation. This demonstrates that RAGE is essential for SI OOB induced signal transduction and angiogenic activity. Signalling studies showed that MAPK and AKT were less phosphorylated in RAGE knocked-down cells compared to controls with SI OOB treatment resulting in less NFK,B activation and pro-inflammatory cytokines. Caspase-3 was activated after prolonged exposure to SI OOB indicating that SI 00-RAGE mediates RPE apoptosis. This data was further supported by microarray analysis of the same group of cells. Overall, this thesis supports the hypothesis that RAGE plays an important role in RPE dysfunction and several inflammation-mediated aspects of AMD. At least in part, RAGE activation is mediated through SI OOB . This axis could play a hitherto unrecognised role in RPE age-related dysfunction and, importantly, the pathogenesis of AMD.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available