The lacrimal glands play an essential role in maintenance of the health of the ocular surface. The lacrimal gland fluid provides the ocular surface with lubrication, anti-bacterial proteins, electrolytes and nutrients. Deficits in lacrimal gland function set the stage for diseases, such as keratoconjunctivitis sicca, a disease that occurs more often in women than in men. The development of rational therapy for dry eye diseases requires a thorough understanding of normal lacrimal gland function. The proposed work will test the hypotheses that the lacrimal gland transports, metabolizes and secretes vitamin A which is required by the ocular surface epithelium and that retinoids (vitamin A derivatives) are required for maintenance of lacrimal gland structure and function.
The specific aims of the proposed research are to: 1) characterize the enzymes that synthesize and hydrolyse retinyl esters in the lacrimal gland with emphasis of the control of these enzymes by cellular retinol binding protein. This will be accomplished by measuring the activity of lecithin:retinol acyltransferase and retinyl ester hydrolase in lacrimal glands of rabbits and rats and determining the effects of cellular retinol binding protein on the activity of these enzymes. 2) Determine whether nuclear retinoic acid receptors are present in the lacrimal gland and cornea and to study the effect of retinoids on the expression these receptors. This will be accomplished by probing tissues and cultured cells of rats and rabbits for the messenger RNA for these receptors, and detection of the receptors by binding assays and antibodies. 3) Characterize the function of lacrimal gland cells with emphasis on the role of retinoids by studying the effects of retinoic acid on the growth, differentiation, and metabolism of these cells in culture. These cells will also be probed for the mRNA for retinoid binding protein. 4) Characterize retinoid metabolism in human lacrimal gland. This will be accomplished by measurement of the activity of enzymes of retinyl ester metabolism and by probing the human lacrimal gland for mRNA for retinoid binding proteins and nuclear receptors. These experiments will affirm the relevance of the animal data to human lacrimal function. The proposed research will help to elucidate the role of retinoids in lacrimal gland and ocular surface function and thereby will contribute to the overall understanding of the role of nutrition in maintaining normal vision.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Visual Sciences A Study Section (VISA)
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University of Pittsburgh
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Ubels, John L (2005) A retrospective on topical retinoids occasioned by observation of unexpected interactions of retinoic acid with androgens and glucocorticoids in immortalized lacrimal acinar cells. Exp Eye Res 80:281-4
Ubels, John L; Veenstra, Eric; Ditlev, Jonathon et al. (2003) Interactions of testosterone and all-trans retinoic acid in regulation of androgen receptor expression in rat lacrimal gland. Exp Eye Res 77:741-8
Aupperlee, Mark D; Wertz, John T; Ingersoll, Kyle E et al. (2002) Identification of androgen receptors in rabbit lacrimal gland by immunohistochemsitry. Adv Exp Med Biol 506:137-41
Ubels, John L; Wertz, John T; Ingersoll, Kyle E et al. (2002) Down-regulation of androgen receptor expression and inhibition of lacrimal gland cell proliferation by retinoic acid. Exp Eye Res 75:561-71
Saarloos, M N; Husa, M R; Jackson 2nd, R S et al. (1999) Intermediate filament, laminin and integrin expression in lacrimal gland acinar cells: comparison of an immortalized cell line to primary cells, and their response to retinoic acid. Curr Eye Res 19:439-49
Ubels, J L; Dennis, M; Lantz, W (1994) The influence of retinoic acid on growth and morphology of rat exorbital lacrimal gland acinar cells in culture. Curr Eye Res 13:441-9
Ubels, J L; Harkema, J R (1994) The rabbit lacrimal gland in vitamin A deficiency. Invest Ophthalmol Vis Sci 35:1249-53
Perkovich, C L; Ubels, J L; Lee, S Y et al. (1993) Cellular retinol-binding protein and cellular retinoic acid-binding protein in the lacrimal gland. Exp Eye Res 56:513-9
Bernal, D L; Ubels, J L (1992) Retinyl ester hydrolysis in the rabbit lacrimal gland. Curr Eye Res 11:889-98
Lopez Bernal, D; Ubels, J L (1992) Bile salt-independent retinyl ester hydrolase in the rat lacrimal gland. Int J Vitam Nutr Res 62:186-90

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