Oxidative stress to cells of the outer retina may be directly involved in the pathogenesis of age-related macular degeneration (AMD). In vitro, oxidative stress directly elevates FGF-2 gene expression in the retinal pigment epithelium (RPE) and in vivo a variety of stresses including toxic light damage and trauma also elevate FGF-2 gene expression in the outer retina. Because FGF-2 is a trophic factor, it may rescue cells of the outer retina from damage caused by oxidative stress. Several studies have shown that aged cells have an altered transcriptional response to oxidative stress. A diminished ability of aged RPE to elevate FGF-2 gene expression in response to oxidative stress might therefore have a direct functional role in the pathogenesis of AMD. We hypothesize that the expression of FGF-2 in response to oxidative stress is regulated through the AP-1 site of the FGF- 2 gene promoter, and that this response is diminished in aged cells due to the reduced function of the AP-1 complex. In the first aim of this proposal, we will investigate the quantitative relationships between oxidative stress and FGF-2 gene expression.
The second aim will investigate DNA response elements and transcription factors which regulate the activity of the FGF-2 gene promoter in response to oxidative stress, and the third aim will specifically explore how RPE aging in vivo diminishes the expression of FGF-2 in response to oxidative stress. Our hypothesis provides a plausible link between cell death in the outer retina and the events of oxidative stress and RPE aging and may provide new approaches for the understanding and treatment of AMD.
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