ISOPRENOID METABOLISM IN THE RETINA

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DESCRIPTION (provided by applicant): The long-range goal of this project is to determine the biological roles of cholesterol (CHOL) and related molecules in the retina in both normal and pathological states. Oxygenated derivatives of CHOL and other sterols occur naturally in cells and tissues, being formed both by autoxidation as well as enzymatically. Such "oxysterols" regulate normal cellular physiology, but also are potent cytotoxins that have been implicated in diseases such as atherosclerosis, diabetes, and cancer. The involvement of oxysterols in retinal diseases is unknown and has yet to be investigated. However, given the association between hypercholesterolemia and atherosclerosis as risk factors in prevalent retinal diseases such as age-related macular degeneration (AMD), research in this area seems warranted. Herein, we evaluate the formation and biological activity of oxysterols in the retina of normal rats in comparison with those that have been treated with a drug (AY9944) that causes accumulation of 7-dehydrocholesterol (7DHC) in the retina and other tissues. AY9944-treated rats are an animal model for the Smith-Lemli-Opitz syndrome (SLOS), a common, autosomal recessive disease with associated ophthalmic defects, including retinal dysfunction. New results presented herein show that AY9944-treated rats develop retinal dysfunction prior to obvious histological damage, yet when exposed to intense green light for only 24 h, a massive, rapid retinal degeneration ensues that is much more severe and extensive than occurs in normal rats under the same conditions. We will examine the time course of retinal degeneration in AY9944-treated rats relative to controls, in both normal, dim cyclic lighting and with the "light damage" paradigm, correlating retinal structure and function with the formation, amounts, and types of oxysterols in the retina. We will compare the effects of intravitreally-injected oxysterols on the structure and function of the retina in normal rats, with and without pretreatment with dimethylthiourea (DMTU), a potent antioxidant. We also will evaluate the ability of DMTU pretreatment to reduce or prevent both oxysterol formation and the retinal damage observed in AY9944-treated and normal rats following exposure to intense green light.