Biochemistry and Pharmacology of the Macular Carotenoids

黄斑类胡萝卜素的生物化学和药理学

• 批准号: 6889874
• 负责人: PAUL STEVEN BERNSTEIN
• 金额: $ 29.9万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6889874
• 关键词: Raman spectrometry; Rana; SDS polyacrylamide gel electrophoresis; animal tissue; binding proteins; binding sites; biological transport; biotransformation; carotenoids; clinical research; enzyme activity; eye pharmacology; glutathione transferase; human tissue; imaging /visualization /scanning; liquid chromatography mass spectrometry; macular degeneration; matrix assisted laser desorption ionization; pharmacokinetics; protein protein interaction; quail; retina; visual pigments

DESCRIPTION (provided by applicant): There is growing awareness that lutein and zeaxanthin may be 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 anti-oxidant and light-screening mechanisms. Whenever a tissue exhibits selective uptake of a compound, the process is likely to be mediated through specific binding proteins, and detailed analysis of carotenoid oxidation products in the eye suggests that the retina is a site for active metabolic interconversions of dietary lutein and zeaxanthin and their metabolites. The enzymes and binding proteins involved in these pathways will be characterized and isolated from human donor eyes. Particular emphasis will be placed on the pi isoform of glutathione S-transferase (GSTP1), an enzyme recently identified in this laboratory as likely to be involved in the conversion of lutein to zeaxanthin in the human eye. Defects in carotenoid binding and metabolic pathways could have severe consequences on normal macular function. Stable isotope methods will be used to study the phamacokinetics of carotenoid uptake, clearance, and metabolism in the eyes of small animal models. 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 has proven to be a powerful objective method for the noninvasive assessment of macular carotenoid levels. An imaging mode of this technique will be used to map the distribution of carotenoids in human donor eyes and in the primate retina with previously unobtainable resolution and specificity. This information will provide valuable insights into the physiology of the macular pigments in the normal eye and a greater understanding of the alterations that may occur in association with aging and degenerative processes.

描述（由申请人提供）：越来越意识到，叶黄素和玉米黄蛋白可能是重要的保护因素，以防止与年龄相关的黄斑变性（AMD）视觉丧失，这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仅从饮食中得出，它们在人类黄斑中的水平很高，其特异性非常高。人们认为它们可以通过抗氧化剂和光筛分机制来防止与年龄相关的黄斑损害。 每当组织表现出选择性摄取化合物时，该过程都可能通过特定的结合蛋白介导，并且眼睛中类胡萝卜素氧化产物的详细分析表明，视网膜是现有饮食中饮食叶黄素和Zeaxanthin及其代谢物的现有代谢相互转换的位点。这些途径中涉及的酶和结合蛋白将被表征并从人类的供体眼中分离出来。特别重点将放在谷胱甘肽S-转移酶（GSTP1）的PI同工型上，该酶最近在该实验室中鉴定出来，因为它很可能参与了人眼中的叶黄素转化为玉米黄质的酶。类胡萝卜素结合和代谢途径的缺陷可能会对正常的黄斑功能产生严重的影响。 稳定的同位素方法将用于研究小动物模型眼中类胡萝卜素摄取，清除和代谢的phamacokinics。这些研究可能会导致改善和更合理的策略，以提高有AMD视觉损失风险的个体中黄斑类胡萝卜素水平。 共振拉曼光谱已被证明是对黄斑类胡萝卜素水平无创评估的有力客观方法。该技术的成像模式将用于绘制类胡萝卜素在人类捐赠者眼中的分布以及以前无法获得的分辨率和特异性的灵长类动物视网膜中的分布。该信息将为正常眼中黄斑色素的生理学提供宝贵的见解，并对与衰老和退化过程有关的改变有更多的了解。