Project Abstract Angiogenesis, the formation of new blood vessels, is a regulated process determined by the local balance of endogenous stimulators versus inhibitors. Angiogenesis-dependent diseases are the major cause of blindness in the developed world. Epidemiological studies have shown that the incidence of exudative age-related macular degeneration (ARMD) is race dependent and highly correlated to pigmentation levels. Compared to white people, lowly-pigmented individuals, the prevalence of choroidal neovascularization is 55% lower in black people, highly-pigmented individuals and 46% lower in Asian Americans. The studies outlined in our proposal are aimed at understanding the role of melanocytes in ARMD. We have previously shown that melanocytes with low pigmentation have high expression levels of a novel angiogenic factor known as Fibromodulin (FMOD). We have confirmed FMOD's angiogenic activity in several in vivo angiogenesis models. The goal of this project is to elucidate the cellular mechanisms by which melanocytes induce pathological angiogenesis via FMOD. We now propose to: (1) Investigate the physiological conditions and molecular stimulators that increase FMOD expression by melanocytes, including identification of transcription factors that activate FMOD expression; (2) Investigate FMOD receptor-mediated signal transduction in angiogenesis by characterizing the FMOD - ROR2 interaction in endothelial cells; and (3) Establish how melanocytes promote angiogenesis via FMOD in various ocular animal models and human donor eyes. Understanding the role of melanocytes and melanocyte-secreted FMOD in vascular diseases would advance our understanding of the melanocytic microenvironment and offer novel targets for personalized treatment of angiogenesis-dependent diseases.