Abstract Glaucoma is a group of age-related neurodegenerative diseases characterized by loss of retinal ganglion cells and their axons. Because RGCs are post-mitotic neurons, their loss is permanent and causes a gradual decline leading toward irreversible blindness. Unfortunately, glaucoma manifests in a way that damages US society more broadly—it disproportionately affects certain racial groups. Glaucoma is a worse problem amongst African Americans than Caucasians. Though socioeconomic factors often contribute to this disparity, a large part is biological and driven by genomic differences between racial groups. A recent breakthrough points to APBB2 as central to glaucoma in African Americans. A large genome-wide association study (GWAS) has found a single nucleotide polymorphism in APBB2 (rs59892895) with genome-wide significance (P=2x10-8; Odds ratio=1.33), and successfully replicated the finding in additional cohorts. identified a variant in the APBB2 gene as an important cause of glaucoma in people of African descent. ABPP2 encodes a cytoplasmic adaptor protein with multiple protein-protein interaction domains. Remarkably, the high-risk allele is present in approximately 21% of African Americans and apparently absent from Caucasians. Our team has contributed to this discovery of APBB2 as a gene of importance to glaucoma in African Americans, and as additionally shown in our Preliminary Data, have developed a hypothesis that overexpression of APBB2 is the disease-causing mechanism. To test this new hypothesis, we recently generated and now have in hand, a mouse model on a pure C57BL/6J genetic background that is overexpressing Apbb2. The strain was created by the University of Iowa Genome Editing Facility and features a full-length mouse Apbb2 (transcript variant 1) under control of a ubiquitous promotor (CAG) and includes a 6His/3XFlag attached to the N-terminus (abbreviated as B6- Tg(Apbb2). The experiments of this proposal utilize this new strain as a central resource to complete the important, but somewhat high risk, test via manipulation that over-expression of Apbb2 promotes glaucoma. In Specific Aim 1, we propose to test the anatomical and physiological consequences over time of Apbb2 overexpression in mice. This Aim will also complete a thorough characterization of the B6-Tg(Apbb2) strain. Specific Aim 2 will study APBB2 from a molecular perspective, identifying retinal APBB2 binding partners that will guide future mechanistic and candidate-driven genetic experiments.