Eicosanoids are ubiquitous biological substances which have many potent actions throughout the body. In the eye, two classes of eicosanoids, prostaglandins and leukotrienes, are thought to be mediators of inflammation and may contribute to the regulation of intraocular pressure. Topically administered prostaglandins reduce intraocular pressure in man, most likely by increasing uveoscleral outflow. The role of these agents in the pharmacologic treatment of glaucoma is being evaluated. Further, the intraocular pressure- lowering effects of other drugs, such as epinephrine, can be accounted for, in part, by their effects on uveoscleral outflow; this effect may be mediated endogenously-produced prostaglandins. In the proposed studies, we will evaluate eicosanoid formation, metabolism and action in tissues of the inflow and outflow pathways of the eye and its modulation by pharmacologic agents used in the treatment of glaucoma, other substances, flow and laser irradiation. Trabecular meshwork and ciliary muscle, and cells derived from these tissues, will be incubated in the presence and absence of radiolabeled arachidonic acid; the products formed will be measured either by radioimmunoassay or by conversion of radiolabeled substrate after separation of products by high performance liquid chromatography. These studies also will evaluate the modulation of eicosanoid biosynthesis by phospholipase A2 and C and the role of cyclic nucleotides and calcium in these cellular processes. Since drugs that increase uveoscleral outflow may do so by direct effects on the ciliary muscle, we will evaluate the morphology of the ciliary muscle, the proposed site of action of prostaglandins, using light and electron microscopic methods. The results of these studies will enhance our understanding of glaucoma (particularly primary open-angle, inflammatory and steroid glaucoma) and its treatment with pharmacologic agents and the laser. These studies also are relevant to our understanding of uveitis and its treatment with anti-inflammatory drugs.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY005990-08
Application #
3261849
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1985-08-01
Project End
1994-07-31
Budget Start
1992-08-01
Budget End
1994-07-31
Support Year
8
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Lindsey, James D; Hofer, Anthony; Wright, Kristine N et al. (2009) Partitioning of the aqueous outflow in rat eyes. Invest Ophthalmol Vis Sci 50:5754-8
Dai, Yi; Lindsey, James D; Duong-Polk, Xuandao et al. (2009) Outflow facility in mice with a targeted type I collagen mutation. Invest Ophthalmol Vis Sci 50:5749-53
Ju, Won-Kyu; Kim, Keun-Young; Lindsey, James D et al. (2008) Intraocular pressure elevation induces mitochondrial fission and triggers OPA1 release in glaucomatous optic nerve. Invest Ophthalmol Vis Sci 49:4903-11
Aihara, Makoto; Lindsey, James D; Weinreb, Robert N (2008) Effect on diurnal intraocular pressure variation of eliminating the alpha-2 adrenergic receptor subtypes in the mouse. Invest Ophthalmol Vis Sci 49:929-33
Lindsey, J D; To, H D; Weinreb, R N (1994) Induction of c-fos by prostaglandin F2 alpha in human ciliary smooth muscle cells. Invest Ophthalmol Vis Sci 35:242-50
Wang, T H; Lindsey, J D; Weinreb, R N (1994) Laminin subtype distribution in the human ciliary body. Invest Ophthalmol Vis Sci 35:3776-82
Weinreb, R N; Kim, D M; Lindsey, J D (1992) Propagation of ciliary smooth muscle cells in vitro and effects of prostaglandin F2 alpha on calcium efflux. Invest Ophthalmol Vis Sci 33:2679-86
Dreher, A W; Weinreb, R N (1991) Accuracy of topographic measurements in a model eye with the laser tomographic scanner. Invest Ophthalmol Vis Sci 32:2992-6
Weinreb, R N; Jeng, S; Miller, A L (1991) Lysosomal enzyme activity in human aqueous humor. Clin Chim Acta 199:1-5
Dreher, A W; Tso, P C; Weinreb, R N (1991) Reproducibility of topographic measurements of the normal and glaucomatous optic nerve head with the laser tomographic scanner. Am J Ophthalmol 111:221-9

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