Project Summary Bruch’s membrane (BrM) represents a small portion of the human eye, yet its role in maintaining ocular health through regulating the transport of macromolecules and nutrients between the retinal pigmented epithelium (RPE), BrM, and choroid, is vastly larger. To highlight this fact, mutations in select proteins involved in forming one of the layers of BrM, the RPE basal lamina (BL), are linked to a spectrum of early- and late-onset macular diseases resembling age-related macular degeneration (AMD). For example, an autosomal dominant R345W mutation in fibulin-3 (F3, aka EFEMP1), a key RPE-BL protein, triggers Doyne Honeycomb Retinal Dystrophy/Malattia Leventinese (DHRD/ML), an aggressive macular dystrophy that closely resembles dry AMD. We hypothesize that F3 contributes to the formation of sub-RPE basal deposits (drusen in humans, basal laminar deposits [BLamD] in mice, and sub-RPE basal deposits in RPE culture systems). The long-term goal of our research effort is to develop tractable F3-centric therapeutics for AMD and DHRD/ML. To accomplish this goal, we will: i) test a promising drug-based anti-inflammatory strategy targeting BLamDs, ii) develop a higher fidelity F3-based degenerative mouse model, enabling better therapeutic testing, and iii) identify RPE protein quality control pathways that regulate F3 protein homeostasis. Successful completion of this project will positively impact our knowledge of this important ECM protein and will provide additional tools and actionable information for interrogating/restoring the intricate biology underlying incurable age-related and inherited eye diseases.