Browsing Department of Biochemistry and Molecular Biology Theses and Dissertations by Subjects
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The Role of GPR109A in NAD+ Metabolism in Aging RPEAge-related macular degeneration (AMD) is the leading cause of blindness in people over the age of 50 worldwide. The retinal pigment epithelium (RPE), located in the back of the eye, is most affected in AMD. Nicotinamide adenine dinucleotide (NAD+) is a coenzyme common to most metabolic pathways. Reductions in NAD+ and NAD+- dependent enzymes (e.g., SIRT1) have been linked causally to the development/progression of many age-related pathologies. None, however, have evaluated NAD+ directly or the mechanisms governing its biosynthesis and related availability in RPE. In our previous study, we have shown that NAD+ levels decline with age in the RPE. This correlated directly with decreased nicotinamide phosphoribosyltransferase (NAMPT) expression. SIRT1 expression and activity was also significantly reduced. Using the human RPE cell line, ARPE-19, primary mouse RPE cells and FK866, a highly specific, noncompetitive NAMPT inhibitor, we simulated in vitro the age-dependent decline in NAD+ and the related increase in RPE senescence. Using this model, we demonstrated the positive impact that therapies that provide supplemental or alternate energy sources such as nicotinamide mononucleotide (NMN) and β-hydroxybutyrate (B-HB) have on RPE viability and the possible role of G-protein coupled receptor, GPR109A in this process.