How Metabolic Stress Can Drive Macular Degeneration

This project explores how abnormal complement activity within the RPE disrupts its metabolism and structural integrity, potentially causing RPE atrophy and triggering vision loss in dry AMD.

Age-related macular degeneration (AMD) is caused by damage to the retinal pigment epithelium (RPE), which nourishes and supports the retina. Chronic inflammation, lipid accumulation, and mitochondrial injury act together to compromise RPE health, but exactly how this occurs is not well understood. This research proposes to identify the key players in this process by focusing on a protein called STAT3, which is a master regulator of cell health, and investigate whether it can be a drug target in AMD.

Our study investigates how intracellular complement activation within the RPE triggers metabolic and structural damage in the retina as a precursor to vision loss. Targeting the C3a-C3aR-STAT3 axis could offer a new treatment avenue for AMD, which currently has limited effective therapies.

Currently, the only approved drugs for dry AMD are complement inhibitors that have limited benefit as they do not slow the rate of vision loss. Our study addresses how intracellular complement activation i.e., within the RPE compromises RPE structural and function integrity and subsequently photoreceptor function. This research could not only identify novel therapeutic targets for dry AMD but also explain why current strategies fall short.