Nuclear receptor driven mechanisms in aging and AMD

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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) cells, resulting in their progressive dysfunction and subsequent atrophy in AMD, are still not known. However, candidate pathogenic pathways linked to 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. However, targeting a potential master regulator of these pathways is one avenue to pursue. Our overarching goal is to discover molecular mechanisms by which nuclear receptors modulate pathologies characteristic of AMD. In this proposal we concentrate on investigating the biology and function of NURR1 (NR4A1, Nuclear Receptor Related-1 protein), an orphan nuclear receptor, in cells vulnerable in AMD. Studies of the central nervous system as well as some systemic diseases have revealed NURR1 as a regulator of a variety of biological processes including cellular proliferation, differentiation, apoptosis, inflammation, lipid homeostasis and metabolism, highlighting its importance in overall cell health. However, as a nuclear receptor, its role has also been shown to vary and be ligand and cell/tissue specific. Given the overlap between process regulated by NURR1 and those important in the development and progression of AMD, we propose to systematically investigate NURR1’s role and potential for therapeutic targeting in ocular cells including RPE, as this has yet to be discovered. Herein we build on preliminary observations including (1) NURR1 expression in human RPE cells decreases with age; (2) NURR1 accumulates extracellularly in drusen and basal deposits of human AMD donor tissue; (3) NURR1 activation attenuates TNFa-induced RPE epithelial-to-mesenchymal (EMT) transition in vitro; and (4) oral administration of a NURR1 activating ligand ameliorates visual function deficits in a mouse model featuring several dry AMD phenotypes. Our findings collectively support an age-related compromise in NURR1- mechanisms in RPE cellular homeostasis. Based on our preliminary data we propose three specific aims to test the hypothesis that NURR1 represents a therapeutic target for AMD by simultaneously regulating aberrant RPE barrier function, cellular lipid metabolism, and inflammation, in cells vulnerable in AMD.