Oportunidades de Doutoramento @ Laboratório Miguel Seabra

Title: NRF2 as a novel therapeutic target in early and intermediate age-related macular degeneration
 
Age-related macular degeneration (AMD) is the most common blinding disease in the western world and is currently incurable. The primary cause of pathology appears to be retinal pigment epithelium (RPE) thinning, accumulation of autofluorescence (lipofuscin) and depigmentation, leading to atrophy and accumulation of extracellular deposits called drusen, between the RPE and the choroid. The RPE is responsible for the daily digestion of photoreceptor outer segments (POS), which imposes a heavy continuous burden on the lysosomal network. We have developed a model system that recapitulates some AMD features in vitro; feeding RPE monolayers in culture with POS leads to accumulation of autofluorescent granules similar to lipofuscin in vivo, resembling RPE stress and disease. Notably, over-expression of the transcriptional regulators TFEB and NFE2L2/NRF2 can prevent the formation and/or resolve autofluorescent granules. We will first test pharmacological NRF2 activators in our RPE models, focusing on repurposing clinically tested drugs. Concomitantly, we will dissect the molecular mechanisms underlying the prevention and/or clearance of autofluorescent granule load in RPE models by macroautophagy and the anti-oxidative stress response. Lead compounds resulting from the above studies will be validated in mouse models of AMD. Overall, this project brings together a unique combination of expertise in a translational effort towards an important medical unmet need to delay AMD progression.