Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor super family of ligand-activated transcription factors. Three subtypes, PPAR-a, PPAR-?/d 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-?/d, as potential therapeutic targets. All three PPARs are expressed in vascular endothelium. In this context, PPAR-a and PPAR-? generally demonstrate anti-inflammatory, anti-proliferative, and anti-angiogenic effects. In contrast, much less is known regarding PPAR-?/d, 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 Muller 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-?/d, 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-?/d is activated in Muller 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-?/d in retinal vascular disease: 1) comparisons of cells isolated from wild type and PPAR-?/d-/- mice;2) highly selective agonists and antagonists in cells isolated from wild type mice;3) comparisons of wild type and PPAR-?/d-/- 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.

Public Health Relevance

We propose to investigate the role of peroxisome proliferator-activated receptor- ?/d (PPAR- ?/d) in early and late stages of retinal vascular pathology related to diabetic retinopathy. Published studies, combined with our preliminary data, strongly implicate PPAR- ?/d 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- ?/d-/- mice to gain insight into the role of PPAR- ?/d in retinal vascular disease.
Our final aim will be to determine the therapeutic efficacy of PPAR- ?/d -specific antagonism in relevant animal models of retinal vascular disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY007533-25
Application #
8128500
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
Project Start
1988-04-01
Project End
2014-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
25
Fiscal Year
2011
Total Cost
$374,400
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Uddin, Md Imam; Evans, Stephanie M; Craft, Jason R et al. (2016) In Vivo Imaging of Retinal Hypoxia in a Model of Oxygen-Induced Retinopathy. Sci Rep 6:31011
Xu, Lili; Ruan, Guoxiang; Dai, Heng et al. (2016) Mammalian retinal Müller cells have circadian clock function. Mol Vis 22:275-83
Capozzi, Megan E; McCollum, Gary W; Cousins, David B et al. (2016) Linoleic Acid is a Diabetes-relevant Stimulator of Retinal Inflammation in Human Retinal Muller Cells and Microvascular Endothelial Cells. J Diabetes Metab 7:
Capozzi, Megan E; Hammer, Sandra S; McCollum, Gary W et al. (2016) Epoxygenated Fatty Acids Inhibit Retinal Vascular Inflammation. Sci Rep 6:39211
Suarez, Sandra; McCollum, Gary W; Jayagopal, Ashwath et al. (2015) High Glucose-induced Retinal Pericyte Apoptosis Depends on Association of GAPDH and Siah1. J Biol Chem 290:28311-20
Savage, Sara R; McCollum, Gary W; Yang, Rong et al. (2015) RNA-seq identifies a role for the PPAR?/? inverse agonist GSK0660 in the regulation of TNF?-induced cytokine signaling in retinal endothelial cells. Mol Vis 21:568-76
Savage, Sara R; Bretz, Colin A; Penn, John S (2015) RNA-Seq reveals a role for NFAT-signaling in human retinal microvascular endothelial cells treated with TNF?. PLoS One 10:e0116941
Barnett, Joshua M; Suarez, Sandra; McCollum, Gary W et al. (2014) Endoglin promotes angiogenesis in cell- and animal-based models of retinal neovascularization. Invest Ophthalmol Vis Sci 55:6490-8
Capozzi, Megan E; McCollum, Gary W; Penn, John S (2014) The role of cytochrome P450 epoxygenases in retinal angiogenesis. Invest Ophthalmol Vis Sci 55:4253-60
Suarez, Sandra; McCollum, Gary W; Bretz, Colin A et al. (2014) Modulation of VEGF-induced retinal vascular permeability by peroxisome proliferator-activated receptor-?/?. Invest Ophthalmol Vis Sci 55:8232-40

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