Macular Degeneration, Metabolism, and a Novel Mitigation Strategy
We utilize a disease model where photoreceptor metabolic adaptations are a contributing factor to early and advanced AMD pathologies. By coupling this model with advanced techniques in metabolomics, mitochondrial assays, and genetic and pharmacologic tools to modulate metabolic targets in photoreceptors, we expect to reveal how age-related shifts in photoreceptor metabolism promote the bioenergetic crisis that drives AMD and to uncover novel therapeutic targets that link photoreceptor metabolism and AMD pathologies to potentially transform how this blinding disease is treated.
This proposal substantially departs from previous work, which focused on the role of RPE in the bioenergetic crisis that drives AMD. It examines the contribution of photoreceptor metabolism to this outer retinal crisis and dissects downstream pathways of mTORC1 key to AMD pathogenesis. Experiments in this project will provide an in vivo, disease-relevant view of outer retinal metabolism in an AMD model, investigate the outer retinal metabolic microenvironment as a driver of immune dysregulation in AMD, and reveal the significance of modulating a metabolic target important in AMD.
The fundamental understanding obtained in this study of how photoreceptor metabolic adaptations uncouple the outer retinal metabolic ecosystem in AMD will address a critical knowledge gap and identify molecular pathways in photoreceptors that contribute to AMD to reveal novel therapeutic targets. To this end, this study will additionally reveal the significance of modulating a metabolic target thought important in AMD, which is expected to open new therapeutic opportunities to treat patients.