Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcription factors. Three subtypes, PPAR-?, PPAR-?/? and PPAR-?, each encoded by a single gene, have been identified. PPARs can be activated by a variety of ligands that include naturally occurring fatty acids, fibrates and prostaglandins. During the last project period, our studies of the roles of prostaglandins in retinal angiogenesis identified PPARs, specifically PPAR-?/?, as potential therapeutic targets. All three PPARs are expressed in vascular endothelium. In this context, PPAR-? and PPAR-? generally demonstrate anti-inflammatory, anti-proliferative, and anti-angiogenic effects. In contrast, much less is known regarding PPAR-?/?, although it has been shown to stimulate proliferation of vascular endothelial cells, and its activation leads to VEGF induction in some cancer cell lines, but not others. Previous work clearly suggests that all three PPARs influence vascular function by highly pleiotropic mechanisms that are tissue- and cell- specific. Thus, in order to understand these mechanisms in the context of retinal angiogenesis, PPAR expression and activation must be characterized in the specific retinal cells that are involved. These cells are the M?ller cells, which produce angiogenic factors, and the retinal microvascular endothelial cells (RMEC), which respond to the angiogenic factors. Using primary cultures of these two cell types, the complicated interactions between PPAR-?/?, growth factor production and angiogenic cell behaviors can be studied systematically, leading to the identification of appropriate therapeutic manipulations of PPARs. Our preliminary data indicate that PPAR-?/? is activated in M?ller cells and RMEC under conditions relevant to both early and late diabetic retinopathy (DR). Thus, we propose to use a combination of tools to characterize the role of PPAR-?/? in retinal vascular disease: 1) comparisons of cells isolated from wild type and PPAR-?/?-/- mice;2) highly selective agonists and antagonists in cells isolated from wild type mice;3) comparisons of wild type and PPAR-?/?-/- mice in models of early and late DR;and 4) highly specific agonists and antagonists in models of DR in wild type mice and in rats. Our in vivo models have been selected for their relevance to early (STZ- induced diabetes) and late (oxygen-induced retinopathy) DR. We believe this strategy is focused and comprehensive, and it will yield information of importance to our fundamental understanding of DR and to the development of rational therapeutic approaches.
We propose to investigate the role of peroxisome proliferator-activated receptor-?/? (PPAR-?/?) in early and late stages of retinal vascular pathology related to diabetic retinopathy. Published studies, combined with our preliminary data, strongly implicate PPAR-?/? in two important pathological processes: retinal production of vascular endothelial growth factor, and retinal vascular endothelial cell proliferation and tubulogenesis. We will exploit our familiarity with appropriate in vitro and in vivo models and our possession of PPAR-?/?-/- mice to gain insight into the role of PPAR-?/? in retinal vascular disease. Our final aim will be to determine the therapeutic efficacy of PPAR-?/?-specific antagonism in relevant animal models of retinal vascular disease.
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