This grant renewal application focuses on understanding the role of lipid-derived oxidative protein and ethanolamine phospholipid modification in eye diseases. Previously we found that (1) prostanoid endoperoxides, generated through cyclo oxygenase or free radical-induced oxidation of arachidonates, rearrange to 3-ketoaldehydes - levuglandins (LGs) and isolevuglandins (isoLGs), respectively - that covalently modify proteins extraordinarily rapidly (within seconds) contributing to pathogenesis, e.g., of glaucoma, and that (2) oxidatively truncated phospholipids containing 3-hydroxyalkenal functional arrays covalently modify proteins to generate carboxyalkyl-pyrrole derivatives. Some of these, e.g., carboxyethyl- pyrroles (CEPs), promote the angiogenesis involved in choroidal neovascularization, the primary cause of severe vision loss in individuals with age-related macular degeneration (AMD). CEPs also foster an immune-mediated atrophy of the retina that recapitulates that of the "dry" form of AMD. To build on these discoveries, we will continue a productive and successful program of strongly collaborative studies. Our immediate goals for the next five years are to understand the involvements of LG/isoLG-ethanolamine phospholipid and -protein modification in eye diseases and develop therapeutic countermeasures by testing the hypotheses that: (1) modification of ethanolamine phospholipids and proteins by LGs/isoLGs accompanies the development of primary open angle glaucoma and AMD and contributes to pathology, and (2) that molecules that act as sacrificial nucleophiles can protect proteins and ethanolamine phospholipids against adduction and crosslinking by LGs/isoLGs in vivo. We also will determine the biological mechanisms of carboxyalkylpyrrole-induced pathology in eye diseases and develop therapeutic counter measures by testing the hypotheses that: (1) carboxyethyl- or carboxy propyl-pyrrole-promoted angiogenesis via TLR2 receptors on endothelial cells contributes to choroidal neovascularization ("wet AMD"), and that anti-CEP Fab or soluble TLR2 fragment "decoy receptors" can therapeutically block this angiogenesis;and (2) T- and B-cell recognition of CEP-modified antigenic peptide(s) contributes to the global retinal atrophy of AMD, and that therapeutic induction of tolerance can blunt this response. Although our mouse models of "wet" and "dry" AMD can yield essential information regarding the specific signaling pathways involved in the onset of disease, there is always the possibility that observations made in the mouse that does not have a macula, may not faithfully recapitulate the human disease, particularly when it comes to therapeutic strategies. To bridge this potential gap, we will develop a better animal model of "dry" AMD. If we succeed in developing a "decoy receptor" drug for treating "wet" AMD we will test its therapeutic efficacy using a laser-induced animal model of choroidal neovascularization.
This project builds on discoveries of specific oxidatively damaged lipids that modify proteins in the eye thereby contributing to the pathology of age-related macular degeneration and glaucoma, eye diseases that diminish the quality of life of millions of Americans. The project seeks to determine the biochemical mechanisms through which the damaged proteins contribute to the disease processes in order to facilitate the rational design of therapeutic countermeasures. The project also seeks to develop drugs that trap the oxidized lipids before they can damage proteins, or that block the interaction of the lipid-modified proteins with receptors that initiate pathological signals which cause growth of capillaries into the retina or cornea, or that blunt the ability of certain immune cells to contribute to retinal degeneration.
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|Wang, Hua; Linetsky, Mikhail; Guo, Junhong et al. (2016) Metabolism of 4-Hydroxy-7-oxo-5-heptenoic Acid (HOHA) Lactone by Retinal Pigmented Epithelial Cells. Chem Res Toxicol 29:1198-210|
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|Wang, Hua; Linetsky, Mikhail; Guo, Junhong et al. (2015) 4-Hydroxy-7-oxo-5-heptenoic Acid (HOHA) Lactone is a Biologically Active Precursor for the Generation of 2-(Ï‰-Carboxyethyl)pyrrole (CEP) Derivatives of Proteins and Ethanolamine Phospholipids. Chem Res Toxicol 28:967-77|
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|Saeed, Ali M; Duffort, Stephanie; Ivanov, Dmitry et al. (2014) The oxidative stress product carboxyethylpyrrole potentiates TLR2/TLR1 inflammatory signaling in macrophages. PLoS One 9:e106421|
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