ISOPRENOID METABOLISM IN THE RETINA

描述（由申请人提供）：本项目的长期目标是 确定胆固醇（CHOL）和相关分子的生物作用， 正常和病理状态下的视网膜。氧化衍生物 胆固醇和其他固醇天然存在于细胞和组织中， 通过自氧化和酶促反应。这种“氧化固醇”调节正常的 细胞生理学，但也是强有力的细胞毒素， 在动脉粥样硬化、糖尿病和癌症等疾病中的作用。的参与 氧固醇在视网膜疾病中的作用是未知的，并且还有待研究。 然而，考虑到高胆固醇血症和动脉粥样硬化之间的联系， 作为流行性视网膜疾病的危险因素， 对于AMD，这方面的研究似乎是必要的。在此，我们评估 正常人视网膜中氧化甾醇的形成及其生物学活性 与用药物（AY 9944）处理的大鼠相比， 导致7-脱氢胆固醇（7 DHC）在视网膜和其他 组织中AY 9944处理的大鼠是Smith-Lemli-Opitz的动物模型。 综合征（SLOS）是一种常见的常染色体隐性遗传疾病， 眼科缺陷，包括视网膜功能障碍。本文介绍的新结果 显示AY 9944处理的大鼠在明显的 组织学损伤，然而当暴露于强烈的绿色光仅24小时时， 大规模的，快速的视网膜变性，这是更严重， 比在相同条件下正常大鼠中发生的广泛。我们将研究 AY 9944处理的大鼠中视网膜变性的时间过程相对于 控制，在正常，昏暗的周期性照明和“光损害” 范例，将视网膜结构和功能与形成相关联， 视网膜中氧化固醇的数量和类型。我们将比较 玻璃体内注射氧固醇对视网膜结构和功能的影响 在正常大鼠中，用和不用二甲基硫脲（DMTU）预处理， 强效抗氧化剂我们还将评估DMTU预处理的能力， 减少或防止氧化固醇形成和在视网膜中观察到的视网膜损伤， 暴露于强绿色光后的AY 9944处理的大鼠和正常大鼠。

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.