Biochemistry and Pharmacology of the Macular Carotenoids

描述（由申请人提供）：叶黄素、玉米黄质和它们的代谢物是膳食叶黄素类胡萝卜素，其特异性地集中在人眼的黄斑中，在那里它们被认为通过多种机制提供针对视网膜变性疾病的保护，所述视网膜变性疾病包括年龄相关性黄斑变性（AMD），所述多种机制包括光毒性蓝光的过滤和活性氧物质的抗氧化剂淬灭。支持它们对AMD的保护作用的证据体已经被认为足够强，以证明将10 mg叶黄素和2 mg玉米黄质包括在本发明的活性治疗组中是合理的。 国家眼科研究所的AREDS2研究。这个正在进行的研究项目的总体目标是提供一个坚实的基础科学研究基础，以解释自然界中600多种类胡萝卜素和血液中约15种类胡萝卜素中的叶黄素和玉米黄质如何以及为什么独特地集中在人眼黄斑中，以便通过这两个具体目标为营养干预提供合理的，基于科学的指导。1）黄斑类胡萝卜素的作用机制和摄取模式的生物化学和成像研究。目前未鉴定的酶（S）负责的独特的饮食转化为叶黄素的内消旋玉米黄质的鉴定和表征将启动和完成，和类胡萝卜素裂解酶BCO1和BCO2在调节类胡萝卜素水平在哺乳动物眼睛中发挥的潜在作用将被探索。利用在构建非侵入性仪器来测量组织中的类胡萝卜素的丰富经验，将构建一个更高分辨率的共焦共振拉曼成像系统，应该允许两个基本问题的眼类胡萝卜素生理学得到回答。黄斑色素类胡萝卜素主要定位于感光轴突或中央凹M？ller细胞？叶黄素和玉米黄质在黄斑中的分布是否不同，如果是， 是否可以推断出两种主要类胡萝卜素的不同生理作用（例如，光过滤与抗氧化剂）？2)类胡萝卜素作用于脊椎动物眼睛的动物模型。除了人类和其他灵长类动物外，没有其他哺乳动物的眼组织吸收超过痕量的类胡萝卜素。在即将到来的赠款期间，类胡萝卜素摄取到啮齿动物组织将优化饮食通过膳食佐剂，上调肠道摄取中度维生素A缺乏症，和杂交育种的各种转基因小鼠靶向类胡萝卜素代谢途径。这些实验的结果将提供对视网膜黄斑的独特进化的见解，并将为研究界提供充分表征的小鼠药代动力学和药效学数据，即在最佳条件下可以将多少叶黄素和玉米黄质递送到啮齿动物视网膜和其他组织。这项工作将有助于小鼠模型研究叶黄素和玉米黄质的生理作用， 防止眼部病变。

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.