PROJECT SUMMARY/ABSTRACT Degeneration or acute damage of retinal pigment epithelial (RPE) and nerve cells in the retina due to Age-related Macular Degeneration (AMD) is a major cause of visual loss and blindness in the United States and worldwide. The proposed multidisciplinary research project will focus on the characterization of a novel signaling pathway for and the development of a novel pharmacological intervention to control degeneration of RPE cells and neurons in AMD. To this end, preclinical testing of the new therapeutic strategy will be performed, along with ocular biotransformation, transport and distribution studies, in established models of human AMD. These experiments will determine efficacy of treatment in terminating and/or preventing AMD associated neuronal loss and preservation of visual function, and to generate data to support feasibility for and move positive findings to phase 1 and 2 clinical trials. Specifically, we will test the two-pronged hypothesis that treatment based on the ocular targeting of a novel chemical antioxidant strategy protects RPE cells and neurons from apoptosis by topical delivery in established models of human AMD and, therefore, leads to prevention or improvement of visual impairment and functional deficits associated with AMD. The determination of neuronal viability and the acquired knowledge on associated biopharmaceutical and pharmacological parameters will indicate the potential of the method to remedy AMD as the overall goal of the project. This novel approach for therapy development in AMD focuses on complementary and alternative cellular protection and neuroprotection. The innovative strategy has the potential to generate a first-in-class pharmacotherapy approach for dry AMD using a topical rather than a systemic or invasive route of drug delivery. The strategy’s potentially high impact lies in its capacity to be both preventative and therapeutic in nature and to complement existing treatment designs and rationales addressing other aspects of AMD treatment such as those targeting neovascularization.