Continuous rapid shuttling of retinoids between photoreceptors and RPE cells during cycles of light and dark exposure is an essential part of the visual cycle. This movement requires transfer of retinoids, which are poorly soluble in water, through an aqueous phase, the interphotoreceptor matrix (IPM). The mechanism(s) of intra- and inter-cellular transport of retinoids in the eye are not known. Several retinoid-binding proteins have been implicated in mediating retinoid transport and in modulating retinoid metabolism in the eye. These proteins are: retinol-binding protein (RBP), the binding protein for vitamin A in blood; the interphotoreceptor matrix retinol-binding protein (IRBP), a soluble protein in IPM that binds retinoids and long chain fatty acids; cellular retinal-binding protein (CRALBP), a unique eye protein with high specificity towards 11-cis-retinoids; and cellular retinol-binding protein I, which binds all-trans retinol and is present in many tissues, including the eye. The main goals of this project are to clarify the factors that regulate movement of retinoids between different locations in the eye and the role(s) of retinoid-binding proteins in transport and metabolism of these compounds. To investigate these questions, the interactions of retinoids with the various environments which they encounter in the eye, i.e., cellular membranes, binding proteins and aqueous spaces, will be studied. The rates by which retinoids move between binding proteins and membranes that are their site of metabolism or are located in the path by which retinoids leave or enter the RPE will be examined. These studies are anticipated to lead to identification of rate-determining steps of retinoid metabolism and the origin of the influence of binding proteins on the activities of enzymes catalyzing retinoid metabolism. The results will also clarify whether uptake and secretion of retinoids by RPE cells occur spontaneously or whether they are facilitated in vivo, and the roles of binding proteins in retinoid transport in the eye.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY009296-06
Application #
2545859
Study Section
Special Emphasis Panel (ZRG1-VISC (01))
Project Start
1992-11-16
Project End
1999-09-29
Budget Start
1997-09-30
Budget End
1998-09-29
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Cornell University
Department
Nutrition
Type
Other Domestic Higher Education
DUNS #
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Shaw, N S; Noy, N (2001) Interphotoreceptor retinoid-binding protein contains three retinoid binding sites. Exp Eye Res 72:183-90
Noy, N (2000) Retinoid-binding proteins: mediators of retinoid action. Biochem J 348 Pt 3:481-95
Noy, N (1998) Measurement of rates of dissociation of retinoids from the interphotoreceptor retinoid-binding protein. Methods Mol Biol 89:177-89
Tschanz, C L; Noy, N (1997) Binding of retinol in both retinoid-binding sites of interphotoreceptor retinoid-binding protein (IRBP) is stabilized mainly by hydrophobic interactions. J Biol Chem 272:30201-7
Chen, Y; Houghton, L A; Brenna, J T et al. (1996) Docosahexaenoic acid modulates the interactions of the interphotoreceptor retinoid-binding protein with 11-cis-retinal. J Biol Chem 271:20507-15
Noy, N; Kelleher, D J; Scotto, A W (1995) Interactions of retinol with lipid bilayers: studies with vesicles of different radii. J Lipid Res 36:375-82
Saari, J C; Bredberg, D L; Noy, N (1994) Control of substrate flow at a branch in the visual cycle. Biochemistry 33:3106-12
Chen, Y; Noy, N (1994) Retinoid specificity of interphotoreceptor retinoid-binding protein. Biochemistry 33:10658-65
Chen, Y; Saari, J C; Noy, N (1993) Interactions of all-trans-retinol and long-chain fatty acids with interphotoreceptor retinoid-binding protein. Biochemistry 32:11311-8
Noy, N; Slosberg, E; Scarlata, S (1992) Interactions of retinol with binding proteins: studies with retinol-binding protein and with transthyretin. Biochemistry 31:11118-24