Biochemistry and Pharmacology of the Macular Carotenoids

说明(申请人提供)：叶黄素、玉米黄质及其代谢物是膳食中的叶黄素类胡萝卜素，专门集中在人眼的黄斑中，被认为可以通过多种机制提供保护，防止视网膜退行性疾病，包括老年性黄斑变性(AMD)，包括过滤光毒性蓝光和抗氧化猝灭活性氧物种。支持它们对AMD的保护作用的证据被认为足够强大，足以证明在AMD的有效治疗臂中包含10毫克的叶黄素和2毫克的玉米黄质 国家眼科研究所的AREDS2研究。这项正在进行的研究项目的总体目标是提供坚实的基础科学研究基础，解释自然界中600多种类胡萝卜素和~15种存在于血液中的叶黄素和玉米黄质是如何以及为什么独特地集中在人眼的黄斑中，以便通过这两个具体目标为针对AMD的营养干预提供合理的、科学的指导：1)对黄斑类胡萝卜素的作用机制和摄取模式的生化和成像研究。目前未知的酶(S)的鉴定和鉴定将开始并完成，该酶负责将饲料中的叶黄素转化为中玉米黄质，并将探索类胡萝卜素裂解酶BCO1和BCO2在调节哺乳动物眼睛中的类胡萝卜素水平方面所起的潜在作用。利用在构建非侵入性仪器测量组织中类胡萝卜素方面的丰富经验，将构建一个更高分辨率的共焦共振拉曼成像系统，该系统应该可以回答眼睛类胡萝卜素生理学的两个基本问题。黄斑色素类胡萝卜素主要定位于光感受器轴突还是中心凹M？ler细胞？叶黄素和玉米黄质在黄斑中的分布是否不同，如果是的话， 能否推断两种主要类胡萝卜素的不同生理作用(例如，光过滤和抗氧化剂)？2)类胡萝卜素在脊椎动物眼睛中作用的动物模型。除了人类和其他灵长类动物外，没有其他哺乳动物将类胡萝卜素摄取到眼睛组织中的量超过了微量。在即将到来的赠款期间，将通过饮食佐剂优化啮齿动物组织对类胡萝卜素的摄取，通过中度维生素A缺乏上调肠道摄取，以及杂交培育针对类胡萝卜素代谢途径的各种转基因小鼠。这些实验的结果将为深入了解视网膜黄斑的独特进化提供见解，并将为研究界提供具有良好特征的小鼠药代动力学和药效学数据，即在最佳条件下，多少叶黄素和玉米黄质可以被输送到啮齿动物的视网膜和其他组织。这项工作将有助于小鼠模型研究叶黄素和玉米黄质在 保护眼睛免受病理性损害。

DESCRIPTION (provided by applicant): Lutein, zeaxanthin, and their metabolites are dietary xanthophyll carotenoids that are specifically concentrated in the macula lutea of the human eye where they are thought to provide protection against degenerative diseases of the retina including age-related macular degeneration (AMD) by multiple mechanisms including filtration of phototoxic blue light and antioxidant quenching of reactive oxygen species. The body of evidence supporting their protective role against AMD has been considered strong enough to justify the inclusion of 10 mg of lutein and 2 mg of zeaxanthin in the active treatment arms of the National Eye Institute's AREDS2 study. The overall goal of this ongoing research project has been to provide a solid basic science research foundation to explain how and why lutein and zeaxanthin out of over 600 carotenoids in nature and ~15 present in the bloodstream are uniquely concentrated in the macula of the human eye in order to provide rational, scientifically based guidance for nutritional interventions against AMD through these two Specific Aims: 1) Biochemical and Imaging studies of the mechanisms of action and modes of uptake of the macular carotenoids. The identification and characterization of the currently unidentified enzyme(s) responsible for the unique conversion of dietary to lutein to meso-zeaxanthin will be initiated and completed, and the potential roles played by the carotenoid cleavage enzymes BCO1 and BCO2 in regulating carotenoid levels in the mammalian eye will be explored. Capitalizing on extensive experience in constructing noninvasive instruments to measure carotenoids in tissues, a higher-resolution confocal resonance Raman imaging system will be constructed that should allow two fundamental questions of ocular carotenoid physiology to be answered. Are the macular pigment carotenoids primarily localized to photoreceptor axons or to foveal M¿ller cells? Are lutein and zeaxanthin differentially distributed in the macula, and if so, can different physiological roles of the two major carotenoids (e.g. light filtration versus antioxidant) be inferred? 2) Animal models of carotenoid action in the vertebrate eye. No other mammals besides humans and fellow primates are known to take up carotenoids into ocular tissues at more than trace amounts. In the upcoming grant period, carotenoid uptake into rodent tissues will be optimized diets through dietary adjuvants, upregulation of intestinal uptake by moderate vitamin A deficiency, and cross breeding of various transgenic mice targeted to the carotenoid metabolic pathways. Results of these experiments will provide insights into the unique evolution of the macula lutea of the retina and will provide the research community with well characterized mouse pharmacokinetic and pharmacodynamic data of how much lutein and zeaxanthin can be delivered to the rodent retina and other tissues under optimal conditions. This work will facilitate mouse model studies of the physiological role of lutein and zeaxanthin in protection against ocular pathology.