Preprostaglandin Endoperoxides

Case Western Reserve University, Cleveland OH

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): 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.