There is growing awareness that lutein and zeaxanthin are 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 antioxidant and light-screening mechanisms. Whenever a tissue exhibits selective uptake of a compound, the process is likely to be mediated through specific binding proteins. A major long-term goal of this project is the identification and characterization of xanthophyll-binding proteins and enzymes in the primate eye. We have identified GSTP1 as the major zeaxanthin-binding protein in the human macula, and we have initial evidence that a specific lutein-binding protein is present as well. Defects in carotenoid binding and metabolic pathways could have severe consequences on normal macular function. Stable isotope methods will be used to study the pharmacokinetics of carotenoid uptake, clearance, and metabolism in the eyes of small animal models such as Japanese quail and transgenic mice overexpressing xanthophyll-binding proteins in their retinas. 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 and lipofuscin autofluorescence attenuation have proven to be powerful objective methods for the noninvasive assessment of macular carotenoid levels. Imaging modes of these techniques will be refined to map the distributions of carotenoids in human donor eyes and in the primate retina with previously unobtained resolution and specificity, and integral modes will be used to perform noninvasive pharmacokinetics in small animal models. Public Health Relevance: The National Eye Institute has devoted considerable resources to the clinical study of carotenoids'roles in protection against AMD in the recently initiated AREDS II study. This grant proposal will provide valuable insights into the physiology of the macular carotenoid pigments in the normal eye and a greater understanding of the alterations that may occur with aging and degenerative processes.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011600-13
Application #
8103937
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
1997-08-01
Project End
2013-02-28
Budget Start
2011-07-01
Budget End
2013-02-28
Support Year
13
Fiscal Year
2011
Total Cost
$357,588
Indirect Cost
Name
University of Utah
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Conrady, Christopher D; Bell, James P; Besch, Brian M et al. (2017) Correlations Between Macular, Skin, and Serum Carotenoids. Invest Ophthalmol Vis Sci 58:3616-3627
Shyam, Rajalekshmy; Gorusupudi, Aruna; Nelson, Kelly et al. (2017) RPE65 has an additional function as the lutein to meso-zeaxanthin isomerase in the vertebrate eye. Proc Natl Acad Sci U S A 114:10882-10887
Li, Binxing; Vachali, Preejith P; Shen, Zhengqing et al. (2017) Retinal accumulation of zeaxanthin, lutein, and ?-carotene in mice deficient in carotenoid cleavage enzymes. Exp Eye Res 159:123-131
Choi, Rene Y; Gorusupudi, Aruna; Wegner, Kimberley et al. (2017) MACULAR PIGMENT DISTRIBUTION RESPONSES TO HIGH-DOSE ZEAXANTHIN SUPPLEMENTATION IN PATIENTS WITH MACULAR TELANGIECTASIA TYPE 2. Retina 37:2238-2247
Shyam, Rajalekshmy; Vachali, Preejith; Gorusupudi, Aruna et al. (2017) All three human scavenger receptor class B proteins can bind and transport all three macular xanthophyll carotenoids. Arch Biochem Biophys 634:21-28
Sripathi, Srinivas R; He, Weilue; Sylvester, O'Donnell et al. (2016) Altered Cytoskeleton as a Mitochondrial Decay Signature in the Retinal Pigment Epithelium. Protein J 35:179-92
Horvath, Martin P; George, Evan W; Tran, Quang T et al. (2016) Structure of the lutein-binding domain of human StARD3 at 1.74?Å resolution and model of a complex with lutein. Acta Crystallogr F Struct Biol Commun 72:609-18
Tanprasertsuk, Jirayu; Li, Binxing; Bernstein, Paul S et al. (2016) Relationship between Concentrations of Lutein and StARD3 among Pediatric and Geriatric Human Brain Tissue. PLoS One 11:e0155488
Vachali, Preejith P; Li, Binxing; Besch, Brian M et al. (2016) Protein-Flavonoid Interaction Studies by a Taylor Dispersion Surface Plasmon Resonance (SPR) Technique: A Novel Method to Assess Biomolecular Interactions. Biosensors (Basel) 6:
Gorusupudi, Aruna; Shyam, Rajalekshmy; Li, Binxing et al. (2016) Developmentally Regulated Production of meso-Zeaxanthin in Chicken Retinal Pigment Epithelium/Choroid and Retina. Invest Ophthalmol Vis Sci 57:1853-61

Showing the most recent 10 out of 48 publications