The NIH Precision Medicine Initiative was launched in 2015 with the goal of improving disease treatment and prevention based on understanding of genes, environment, and lifestyle. As a first step towards this goal, genome-wide association studies (GWAS), funded in part by the NIH, have identified 127 genes associated with risk for developing primary open-angle glaucoma (POAG) across multiple ancestries. However, this has not yet translated into personalized approaches for disease diagnosis, risk stratification, monitoring or treatment of this common, blinding disease. This proposal describes a 5-year training program for a clinician- scientist to develop a career focused on leveraging understanding of the genetic basis of glaucoma to optimize clinical care for afflicted individuals. I am well-suited to tackle this important unmet need. I have a strong research background in glaucoma genetics and continued this work under the mentorship of Dr. Janey Wiggs during my glaucoma fellowship at Mass. Eye and Ear. Our preliminary data demonstrate that POAG patients with high mitochondrial genetic risk scores have higher mean treated intraocular pressure (IOP) and markedly increased prevalence of paracentral field loss compared to patients with low mitochondrial genetic risk. These results suggest that POAG driven by mitochondrial risk variants may represent a distinct disease subtype with specific clinical features. However, the underlying molecular mechanism is unknown and deep clinical phenotyping is also warranted. In Aim 1, we will investigate the extent that individuals with high mitochondrial pathway-specific polygenic risk scores (PRSs) display elevated IOP, retinal mitochondrial dysfunction, distinct visual field loss patterns on archetypal analysis and greater susceptibility to environmental toxins that impact mitochondrial function. In Aim 2, we will characterize the functional impact of mitochondrial gene variants using disease-relevant primary cell strains (trabe