Summary Dry age-related macular degeneration (AMD) is the leading cause of vision loss in the Western World with a complex etiology. The fundamental abnormalities occurring in retinal pigment epithelial (RPE) resulting in their progressive dysfunction and subsequent atrophy in AMD, are still not known. However, candidate pathogenic pathways linked to the development of disease have emerged from the convergence of a sundry of epidemiological, genetic, morphological, and biochemical studies, including inflammation, lipid dysregulation, apoptosis, and RPE barrier dysfunction among others. Currently there are no drugs available to treat dry AMD. In this proposal we concentrate on investigating the biology and function of osteopontin (OPN), a matricellular glycoprotein known for its involvement in the pathogenesis of a variety of neurodegenerative and systemic diseases, in which inflammation is key, in part through its role as a macrophage recruitment and retention factor. However, OPN reportedly plays a two-sided role having both pro- and anti-inflammatory properties. Furthermore, OPN has also been shown to regulate cellular homeostasis effecting cell differentiation, metabolism, autophagy, phagocytosis, and apoptosis to name a few. This potential paradox in the role of OPN may in part be due to the fact that (1) OPN function is cell and tissue specific, and (2) most studies have not delineated the roles of the different OPN isoforms, which include intracellular versus secreted OPN and splice variants OPNa, b, and c. With this in mind, we propose to systematically investigate the role of OPN in AMD vulnerable cells with a focus on RPE biology and test the therapeutic potential of modifying OPN levels in animal models that present with dry ‘AMD-like’ pathologies. Published studies and key preliminary observations that precipitated pursuing this study include (1) circulating soluble OPN (sOPN) levels increase in a subpopulation of individuals with age; (2) the role of intracellular OPN, is less known but associated with amelioration of inflammation; (3) intracellular OPN expression in human RPE cells is decreased in early dry AMD donor tissue; (4) secreted OPN accumulates extracellularly in drusen and basal deposits of human AMD donor tissue; (5) plasma OPN is elevated in late dry AMD patients; and (6) human RPE cells secrete OPN following oxidant injury and are a potential local source. Based on our preliminary data and the known paradoxical anti- and pro-inflammatory roles of OPN in neurodegenerative and systemic diseases that share common pathogenic pathways with AMD, we will test the hypotheses that OPN regulates inflammation, aberrant RPE barrier function, and cell homeostatic mechanisms, in an isoform dependent manner.