Our laboratory is focused on determining the pathogenesis mechanism(s) of age related macular degeneration (AMD). AMD is a complex disease that involves the aging process but is mediated by multiple genetic and environmental factors. The choriocapillaris and Bruch's membrane are known to gradually form lipids deposits as a process of aging. Our hypothesis is that these lipid deposits interfere with the permeability of Bruch's membrane and their oxidation could expose the RPE and choriocapillaris to the cytotoxic effect of the oxidized lipids. There is considerable scientific evidence suggesting that lipid deposits tend oxidize and the oxidized lipids are toxic to a variety of cell types. Another significant problem associated with the accumulation and oxidation of lipids is the involvement of the immune system. Oxysterols and fatty acid peroxides are known to induce potent pharmacological effects on different cell types especially macrophages. Thus, we are focusing our research into understanding lipid transport in and out of the retina and the formation and effects of oxidized lipids. Examination of lipoproteins, lipid transporters and receptors suggests that the retina will uptake lipids from circulating LDL and transport them within the retina as HDL. The lipid efflux also seems to be mediated via RPE synthesized lipoproteins. We have demonstrated that 7-ketocholesterol (the main oxysterol in oxLDL) will induce cell death in the cultured RPE cells by inducing mitochondrial depolarization and cytochrome C spillage. In rats, high doses of circulating oxLDL induce choroidal edema and photoreceptor loss. Photo oxidation is one of the main processes in the formation of oxidized lipids and thus the retina is likely to oxidize lipids in situ. We are also studying proteins that bind oxysterols (OSBPs) and enzymes that hydroxylate (CYP27A1) or sulfate (cholesterol sulfotransferases) oxysterols, especially 7-ketocholesterol, into more hydrophilic and less toxic compounds such as 7-keto-27 hydroxycholesterol and 7-keto-3-sulphocholesterol. Another group of enzymes we are studying are the methionine sulfoxide reductases (MSRs). These enzymes reverse the effects of methionine oxidation in proteins and thus protect the mitochondria and other organelles from the effects of lipid peroxides. In essence, we are trying to assemble the mechanism of lipid transport, oxidation, neutralization and excretion in the retina with the purpose of understanding the pathogenesis of AMD and the development of potential therapeutic targets.
