Biochemistry and Pharmacology of the Macular Carotenoids

项目总结/摘要 黄斑色素类胡萝卜素、叶黄素、玉米黄质和叶黄素的代谢物中位玉米黄质是 独特地集中在灵长类动物的中央凹区域，形成黄斑的黄色色素 它们可以增强视觉功能，防止光诱导的氧化损伤， 与年龄相关性黄斑变性（AMD）和其他视网膜疾病有关。饮食 富含叶黄素和玉米黄质的补充剂是最广泛的处方干预措施之一 对于那些担心未来会因AMD而视力丧失的患者来说，这些叶黄素类胡萝卜素 成为单眼大玻璃疣或晚期AMD患者的标准治疗， AREDS 2结果;然而，在美国，患者和临床医生通常会整合 营养干预纳入临床实践，超出了在大型随机 临床试验如AREDS 2和类胡萝卜素也不例外。例如，叶黄素已经被 在没有任何临床试验的情况下，将其纳入产前补充剂和婴儿配方奶粉， 希望它能促进儿童视觉系统的健康和发育，并非饮食性地 类胡萝卜素如内消旋玉米黄质现在被推广为“下一代AREDS 补充剂”，同样没有充分的临床或基础科学研究。伯恩斯坦实验室是 致力于提供对生物化学，生理学和药理学的机械见解， 黄斑类胡萝卜素，以优化合理，安全的干预措施， 寿命推动实验室研究的关键组织概念是， 人视网膜中央凹区域的三种黄斑类胡萝卜素的保护功能是由 结合蛋白、转运蛋白和代谢酶的复杂、受调节的相互作用。研究 该小组使用综合方法研究了这一前提，其中包括对 类胡萝卜素运输和代谢的酶学和蛋白质生物化学， 利用转基因“黄斑色素小鼠”研究健康和疾病状态下眼内类胡萝卜素的功能 相对于野生型小鼠，经基因工程改造使类胡萝卜素进入视网膜的摄取增强， 和先进的成像技术，特别强调共振拉曼成像， 黄斑类胡萝卜素在前所未有的光谱和空间分辨率。这些研究的结果将 在分子水平上推进其生理功能的机械知识，这将使 说明其在视网膜神经保护中作用的基础研究，以及将 导致合理的，科学支持的治疗决定，以防止视力丧失整个 人的一生。

Project Summary/Abstract The macular pigment carotenoids, lutein, zeaxanthin, and lutein’s metabolite meso-zeaxanthin are uniquely concentrated in the primate foveal region to form the yellow pigment of the macula lutea where they can enhance visual function and protect against the light-induced oxidative damage that has been associated with age-related macular degeneration (AMD) and other disorders of the retina. Diets and supplements enriched in lutein and zeaxanthin are among the most widely prescribed interventions for patients concerned about future visual loss from AMD, and these xanthophyll carotenoids have become standard-of-care for individuals with large drusen or advanced AMD in one eye based on AREDS2 results; however, it is common in the United States for patients and clinicians to integrate nutritional interventions into clinical practice beyond indications established in large, randomized clinical trials such as AREDS2, and carotenoids are no exception. For example, lutein has been incorporated into prenatal supplements and infant formulas without any clinical trials at all, based only on the hope that it might promote health and development of the child’s visual system, and nondietary carotenoids such as meso-zeaxanthin are now being promoted as “next generation AREDS supplements”, again without adequate clinical or basic science studies. The Bernstein laboratory is dedicated to provide mechanistic insights into the biochemistry, physiology, and pharmacology of the macular carotenoids to optimize rational, safe interventions against blinding diseases throughout the lifespan. The key organizing concept that drives the laboratory’s research is that the specific deposition and protective functions of the three macular carotenoids in the human foveal region are mediated by complex, regulated interplay of binding proteins, transporters, and metabolic enzymes. The research group examines this premise using an integrated approach that includes biochemical studies on the enzymology and protein biochemistry of carotenoid transport and metabolism, animal models for carotenoid function in the eye in health and disease using transgenic “macular pigment mice” genetically engineered to have enhanced carotenoid uptake into the retina relative to wild-type mice, and advanced imaging techniques with particular emphasis on resonance Raman imaging to localize the macular carotenoids at unprecedented spectral and spatial resolution. The results of these studies will advance mechanistic knowledge of their physiological functions at a molecular level, which will enable basic studies that account for their roles in retinal neuroprotection, as well as clinical studies that will lead to rational, scientifically supported decisions about treatments to prevent visual loss throughout a person’s lifetime.