Biochemistry and Pharmacology of the Macular Carotenoids

描述（由申请人提供）：人们越来越认识到叶黄素和玉米黄质是防止年龄相关性黄斑变性（AMD）视力丧失的重要保护因素，AMD是发达国家不可逆失明的主要原因。这些叶黄素类胡萝卜素完全来自饮食，它们在人类黄斑中以非常高的水平浓缩，具有非常高的特异性。它们被认为是通过抗氧化和遮光机制来保护黄斑免受与年龄相关的损伤。 每当组织表现出选择性摄取化合物时，该过程可能通过特异性结合蛋白介导。该项目的一个主要长期目标是识别和表征灵长类动物眼中的叶黄素结合蛋白和酶。我们已经确定GST P1作为主要的玉米黄质结合蛋白在人类黄斑，我们有初步的证据表明，一个特定的叶黄素结合蛋白也存在。类胡萝卜素结合和代谢途径的缺陷可能对正常黄斑功能产生严重后果。 稳定同位素方法将被用来研究类胡萝卜素的吸收，清除和代谢的小动物模型，如日本鹌鹑和转基因小鼠在其视网膜中过度表达叶黄素结合蛋白的眼睛的药代动力学。这些研究可能会导致改善和更合理的策略，提高黄斑类胡萝卜素水平的个人在风险的视力丧失从AMD。 共振拉曼光谱和脂褐素自发荧光衰减已被证明是强大的客观方法，用于黄斑类胡萝卜素水平的非侵入性评估。这些技术的成像模式将被细化，以绘制类胡萝卜素在人类供体眼中和灵长类动物视网膜中的分布，具有以前未获得的分辨率和特异性，积分模式将用于在小动物模型中进行非侵入性药代动力学。 公共卫生相关性：在最近启动的AREDS II研究中，国家眼科研究所投入了大量资源用于类胡萝卜素在预防AMD中的作用的临床研究。这项拨款提案将提供宝贵的见解黄斑类胡萝卜素色素在正常的眼睛和更好地了解可能发生的变化与老化和退行性过程的生理。

DESCRIPTION (provided by applicant): There is growing awareness that lutein and zeaxanthin are important protective factors against visual loss from age-related macular degeneration (AMD), the leading cause of irreversible blindness in the developed world. These xanthophyll carotenoids are derived exclusively from the diet, and they are concentrated at very high levels in the human macula with extraordinarily high specificity. They are thought to protect against age-related damage to the macula through antioxidant and light-screening mechanisms. Whenever a tissue exhibits selective uptake of a compound, the process is likely to be mediated through specific binding proteins. A major long-term goal of this project is the identification and characterization of xanthophyll-binding proteins and enzymes in the primate eye. We have identified GSTP1 as the major zeaxanthin-binding protein in the human macula, and we have initial evidence that a specific lutein-binding protein is present as well. Defects in carotenoid binding and metabolic pathways could have severe consequences on normal macular function. Stable isotope methods will be used to study the pharmacokinetics of carotenoid uptake, clearance, and metabolism in the eyes of small animal models such as Japanese quail and transgenic mice overexpressing xanthophyll-binding proteins in their retinas. These studies may lead to improved and more rational strategies for raising macular carotenoid levels in individuals at risk for visual loss from AMD. Resonance Raman spectroscopy and lipofuscin autofluorescence attenuation have proven to be powerful objective methods for the noninvasive assessment of macular carotenoid levels. Imaging modes of these techniques will be refined to map the distributions of carotenoids in human donor eyes and in the primate retina with previously unobtained resolution and specificity, and integral modes will be used to perform noninvasive pharmacokinetics in small animal models. Public Health Relevance: The National Eye Institute has devoted considerable resources to the clinical study of carotenoids' roles in protection against AMD in the recently initiated AREDS II study. This grant proposal will provide valuable insights into the physiology of the macular carotenoid pigments in the normal eye and a greater understanding of the alterations that may occur with aging and degenerative processes.