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.
Even though AREDS2 will not release its results until 2013, dietary supplementation with the macular pigment carotenoids, lutein and zeaxanthin, is widely practiced by individuals at risk for visual loss from age-related macular degeneration (AMD). The overall goal of this project is to elucidate the biochemical mechanisms responsible for the specific uptake of lutein and zeaxanthin into the macula of the human eye and to gain insights into their potential protective mechanisms of action. These basic science results when combined with the clinical outcomes of AREDS2 will provide clinicians and their patients with rational, scientifically supported recommendations for effective nutritional interventions against AMD.
|Vachali, Preejith P; Li, Binxing; Bartschi, Alexis et al. (2015) Surface plasmon resonance (SPR)-based biosensor technology for the quantitative characterization of protein-carotenoid interactions. Arch Biochem Biophys 572:66-72|
|Bernstein, P S; Johnson, E J; Neuringer, M et al. (2014) Comment on: What is meso-zeaxanthin, and where does it come from? Eye (Lond) 28:240-2|
|Vachali, Preejith P; Besch, Brian M; Gonzalez-Fernandez, Federico et al. (2013) Carotenoids as possible interphotoreceptor retinoid-binding protein (IRBP) ligands: a surface plasmon resonance (SPR) based study. Arch Biochem Biophys 539:181-6|
|Scarmo, Stephanie; Cartmel, Brenda; Lin, Haiqun et al. (2013) Single v. multiple measures of skin carotenoids by resonance Raman spectroscopy as a biomarker of usual carotenoid status. Br J Nutr 110:911-7|
|Mayne, Susan T; Cartmel, Brenda; Scarmo, Stephanie et al. (2013) Resonance Raman spectroscopic evaluation of skin carotenoids as a biomarker of carotenoid status for human studies. Arch Biochem Biophys 539:163-70|
|Scarmo, S; Henebery, K; Peracchio, H et al. (2012) Skin carotenoid status measured by resonance Raman spectroscopy as a biomarker of fruit and vegetable intake in preschool children. Eur J Clin Nutr 66:555-60|
|Li, Binxing; Vachali, Preejith; Frederick, Jeanne M et al. (2011) Identification of StARD3 as a lutein-binding protein in the macula of the primate retina. Biochemistry 50:2541-9|
|Neale, Benjamin M; Fagerness, Jesen; Reynolds, Robyn et al. (2010) Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci U S A 107:7395-400|
|Bernstein, Paul S; Delori, Francois C; Richer, Stuart et al. (2010) The value of measurement of macular carotenoid pigment optical densities and distributions in age-related macular degeneration and other retinal disorders. Vision Res 50:716-28|
|Mayne, Susan T; Cartmel, Brenda; Scarmo, Stephanie et al. (2010) Noninvasive assessment of dermal carotenoids as a biomarker of fruit and vegetable intake. Am J Clin Nutr 92:794-800|
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