Glutathione S-Transferase Pi in Age-Related Macular Degeneration

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Project Summary Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in the developed countries. Oxidative damage has been implicated in AMD pathogenesis. The retina has a high oxygen demand and is at risk for light-induced damage because of the complex, active photochemical reactions of vision. Concentrated in the human macula are dietary carotenoid antioxidants lutein and zeaxanthin, and their levels have been found to be lower in AMD compared to elderly control eyes. Recently, the pi isoform of glutathione S-transferase (GSTP1) has been identified as a zeaxanthin-binding protein in the human macula. Glutathione S-transferases are a family of intracellular detoxification enzymes that catalyze the reduction of electrophiles, including reactive oxidative species, by conjugating them to glutathione. GSTP1 has been shown to play a role in oxidative damage, and macular localization of GSTP1 as a zeaxanthin-binding protein suggests that it plays an important role in modulating the levels of antioxidants in the macula. Our preliminary data revealed that GSTP1 expression is decreased in AMD compared to normal elderly control eyes. We hypothesize that decreased expression of GSTP1 renders susceptibility to oxidative stress in the macula, leading to AMD pathogenesis. The long-term goals are to understand the molecular mechanism of AMD pathogenesis and to develop effective preventative and therapeutic strategies. Our hypothesis will be tested with three specific aims. Specific Aim 1 will determine if decreased levels of GSTP1 accompany age and AMD in human retina. Specific Aim 2 will determine whether reduction of the murine counter-part of GSTP1 in mouse retina will mimic the AMD phenotype in mice. Specific Aim 3 will address if GSTP1 over-expression provides protection against oxidative damage in a light-induced retinal damage murine model. The proposed studies will utilize clinical ophthalmic diagnosis, immunohistochemistry, Western analysis, as well as electrophysiology.