Pseudoexfoliation syndrome is a common age-related disease of worldwide significance and is the most commonly identified specific cause of open-angle glaucoma. The disease initiating mechanisms of pseudoexfoliation syndrome are almost completely unknown. Currently, all therapeutic strategies for pseudoexfoliative glaucoma aim to lower IOP and there are no specific therapies aimed at treating pseudoexfoliation syndrome itself. With increased knowledge of the initiating mechanisms, it should be possible to devise improved therapeutic strategies that specifically target pseudoexfoliation syndrome itself, promoting earlier interventions and improved medical outcomes. Our long-term goal is to contribute to the development of improved human glaucoma therapies by utilizing synergistic genetic approaches with mice and humans. Here, we take advantage of a phenotype-driven screening approach among mouse coat color variants that has identified a new mouse model of eye disease that strongly resembles aspects of pseudoexfoliation syndrome. Our objective in this proposal is to capitalize on this resource by initiating mechanistic studies and completing a phenotypic characterization of the strain. Using genetic approaches in mice, we are testing the hypothesis that susceptibility of the eye toward PEX syndrome is mediated via a mechanism influencing cellular morphology and oxidative stress associated with melanogenesis. Suspecting that the same mechanism likely underlies human PEX syndrome, we are simultaneously conducting human genetic association studies. Completion of these studies will not only identify PEX syndrome-related genetic pathways, but will also develop an animal model needed for development and testing of future therapeutic strategies. In the long-term, these experiments will contribute to a better understanding of glaucoma, and ultimately, to improved human therapies. Pseudoexfoliation syndrome is a common age-related disease of worldwide significance and is the most commonly identified specific cause of open-angle glaucoma. Here, we take advantage of a newly identified mouse model that strongly resembles aspects of pseudoexfoliation syndrome. Our objective in this proposal is to test the genetic pathways contributing to phenotypes of this mouse strain and test the significance of these genes among human pseudoexfoliation patients.