Age-related macular degeneration (AMD) is the most common cause of blindness in the developed world. We do not know the cause of the disease, so it is difficult to develop strategies to prevent the disease. For the roughly 10% of AMD patients that develop neovascularization, so called ‘wet’ AMD, we have an effective treatment. 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, so determining why black people appear protected from AMD is still an enigma. In our previous work we have demonstrated that the pigmented support tissue for the retina, the retinal pigment epithelium (RPE), expresses factors that are protective for the retinal photoreceptors, and that the secretion of these factors is linked to the pigmentation of the RPE. In fact, we identified a signaling pathway that both upregulates the most potent neurotrophic factor in the eye (PEDF) and down regulates the angiogenesis stimulating factor (VEGF), two activities likely to protect from AMD. This pathway is through the signaling molecule, GPR143, and we determined that the ligand for this receptor is L-DOPA, an intermediate of the pigmentation pathway. Thus we identified a signaling molecule that controls two RPE activities likely to be protective from AMD, and showed that L-DOPA, part of the pigmentation pathway, could drive both activities. We then asked whether older individuals taking L-DOPA daily for movement disorders are they protected from AMD. Using observational analyses of 3 nonintersecting cohorts, encompassing over 15 million people across the country we found the answer was yes. Those taking L-DOPA are significantly less likely to ever develop AMD (p<0.001), and if they do, they develop the disease significantly later, over 8 years later, p<0.001. The effect was similar for both ‘dry’ and ‘wet’ AMD. Herein we propose to follow-up this critical observation using cell biological studies to determine how the effect of L-DOPA occurs, testing whether intersecting pathways related to dopamine signaling may be the actual driving force behind the protective effect rather than L-DOPA. This is a critical set of experiments because L-DOPA is converted to dopamine in neurons and RPE, and both RPE cells and the retinal neurons have dopamine receptors. The research plan will test whether GPR143 or other dopamine related receptors underlie the protection from AMD observed in those taking L-DOPA, and once identified the receptors responsible can be targeted to develop strategies to protect people from ever developing the disease. Finally, we will conduct the first preclinical, prospective trial to test whether L-DOPA delays or prevents AMD in an animal model.