Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the population over 55 years of age and a major source of chronic disability in the US. However, clinical treatment options that prevent or slow the progression of AMD are extremely limited. Oxidative stress-induced damage to the retinal pigment epithelium (RPE) is thought to be involved in the development of AMD, and preliminary data from our lab suggests that pharmacological inhibition of the enzyme, N-ribosyl-dihydronicotinamide (NRH):quinone oxidoreductase 2 (NQO2), protects human RPE cells from this oxidative stress. While some evidence suggests involvement of antioxidant enzyme induction, the mechanism of this protection is essentially unknown. A better understanding of the mechanism of NQO2-mediated protection is crucial to developing appropriate therapeutic strategies against AMD. In this application, we hypothesize that NQO2 inhibition mediates the resistance against oxidative stress. Secondly, we hypothesize that NQO2 inhibition induces antioxidant enzymes, which is the underlying protective mechanism against oxidative stress. We seek to investigate whether NQO2 inhibition protects RPE cells from oxidative stress (Specific Aim 1). We will also investigate the effect of NQO2 inhibition on the expression of downstream antioxidant enzymes (Specific Aim 2). The long-term goal of this project is to better understand the endogenous pathways involved in the cellular defense mechanisms against oxidative stress in order to determine clinically relevant targets and reduce oxidative stress in the RPE. Ultimately, we hope to identify effective therapeutic approaches to AMD.
The leading cause of blindness in the elderly is age-related macular degeneration (AMD), but current treatment options are extremely limited. Because the damage caused by oxidants in the eye is thought to be involved in the development of AMD, treatment strategies effectively countering oxidants may help slow or prevent the progression of AMD.
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