Age-related macular degeneration (AMD) is the most common cause of blindness in the developed world. Wedo not know the cause of the disease so it is difficult to develop strategies to prevent the disease. For theroughly 10% of AMD patients that develop neovascularization so called wet AMD we have an effectivetreatment. However it requires repeated intraocular injections which are expensive and associated with risks.AMD is much more common in white individuals than black individuals but race is a very complex trait sodetermining why black people appear protected from AMD is still an enigma. In our previous work we havedemonstrated that the pigmented support tissue for the retina the retinal pigment epithelium (RPE) expressesfactors that are protective for the retinal photoreceptors and that the secretion of these factors is linked to thepigmentation of the RPE. In fact we identified a signaling pathway that both upregulates the most potentneurotrophic factor in the eye (PEDF) and down regulates the angiogenesis stimulating factor (VEGF) twoactivities likely to protect from AMD. This pathway is through the signaling molecule GPR143 and wedetermined that the ligand for this receptor is L-DOPA an intermediate of the pigmentation pathway. Thus weidentified a signaling molecule that controls two RPE activities likely to be protective from AMD and showedthat L-DOPA part of the pigmentation pathway could drive both activities. We then asked whether olderindividuals taking L-DOPA daily for movement disorders are they protected from AMD. Using observationalanalyses of 3 nonintersecting cohorts encompassing over 15 million people across the country we found theanswer was yes. Those taking L-DOPA are significantly less likely to ever develop AMD (p<0.001) and if theydo they develop the disease significantly later over 8 years later p<0.001. The effect was similar for both dryand wet AMD. Herein we propose to follow-up this critical observation using cell biological studies todetermine how the effect of L-DOPA occurs testing whether intersecting pathways related to dopaminesignaling may be the actual driving force behind the protective effect rather than L-DOPA. This is a critical setof experiments because L-DOPA is converted to dopamine in neurons and RPE and both RPE cells and theretinal neurons have dopamine receptors. The research plan will test whether GPR143 or other dopaminerelated receptors underlie the protection from AMD observed in those taking L-DOPA and once identified thereceptors responsible can be targeted to develop strategies to protect people from ever developing thedisease. Finally we will conduct the first preclinical prospective trial to test whether L-DOPA delays orprevents AMD in an animal model.