Glaucoma is a blinding eye disease. A major treatment strategy for this disease is the reduction of aqueous humor secretion with B-adrenergic antagonists such as timolol and other drugs. Although such treatments are effective, their molecular mechanisms are largely unknown. An understanding of ion transport mechanisms which underlie aqueous humor secretion and its regulation might lead to improved glaucoma treatment protocols. Considerable evidence suggests that timolol may function as a hypotensive agent by inhibiting diurnal adrenergic elevation of aqueous humor inflow. The PI has reported that Na+, K+, Cl cotransport in ciliary epithelium is stimulated by B adrenergic agents and inhibited by timolol. This is a promising lead in understanding diurnal adrenergic regulation of aqueous humor inflow in humans. The PI proposes to investigate the molecular mechanisms underlying stimulation of Na+, K+, Cl cotransport by adrenergic agonists, including the roles of second messenger pathways and phosphorylation dephosphorylation pathways. He also proposes to test the hypothesis that other hormones known to either increase or decrease aqueous inflow might exert their effects through modulation of Na+, K+, Cl cotransport activity.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY010332-05
Application #
2471217
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1993-12-01
Project End
2001-11-30
Budget Start
1997-12-01
Budget End
1998-11-30
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Dunn, J J; Lytle, C; Crook, R B (2001) Immunolocalization of the Na-K-Cl cotransporter in bovine ciliary epithelium. Invest Ophthalmol Vis Sci 42:343-53
Hochgesand, D H; Dunn, J J; Crook, R B (2001) Catecholaminergic regulation of Na-K-Cl cotransport in pigmented ciliary epithelium: differences between PE and NPE. Exp Eye Res 72:1-12
Bildin, V N; Yang, H; Crook, R B et al. (2000) Adaptation by corneal epithelial cells to chronic hypertonic stress depends on upregulation of Na:K:2Cl cotransporter gene and protein expression and ion transport activity. J Membr Biol 177:41-50
Crook, R B; Takahashi, K; Mead, A et al. (2000) The role of NaKCl cotransport in blood-to-aqueous chloride fluxes across rabbit ciliary epithelium. Invest Ophthalmol Vis Sci 41:2574-83
Riese, K; Beyer, A T; Lui, G M et al. (1998) Dopamine D1 stimulation of Na+,K+,Cl- cotransport in human NPE cells: effects of multiple hormones. Invest Ophthalmol Vis Sci 39:1444-52
Crook, R B; Riese, K (1996) Beta-adrenergic stimulation of Na+, K+, Cl- cotransport in fetal nonpigmented ciliary epithelial cells. Invest Ophthalmol Vis Sci 37:1047-57