Glaucoma is a leading cause of blindness in the U.S. and worldwide that occurs as a result of a loss in retinal ganglion cells and a progressive optic neuropathy. Identification of the causative factors leading to this disease is of great interest. Recently, it has been shown that patients with primary open angle glaucoma (POAG) have an elevation in their aqueous humor endothelin (ET) concentrations. Similarly, in a animal model of glaucoma (Beagles) a four-fold increase in endothelin is seen in the aqueous humor. Our laboratory has been investigating the role of ocular endothelins for several years and recently have shown that it may be playing a role in the pathogenesis of glaucoma based on preliminary observations of its effects on axonal transport and ET's ability to activate the NOS-2/NO pathway. The overall goal of this application is to demonstrate that endothelin is an important ocular derived peptide that is not only involved in IOP and vascular homeostasis, but is a key component in the pathogenesis of glaucoma. The hypothesis to test is that ET is preferentially synthesised and released in the eye and at increasing concentrations mediates a series of events that exert detrimental effects on optic nerve function through decreases in axonal transport and increases in neurotoxic compounds, such as NO. The net effect is to promote retinal ganglion cell death. The following aims are planned to address this hypothesis: 1) Can elevated pressure or neuronal regulation increase endothelin synthesis and release in retinal pigment epithelium (RPE), optic nerve astrocytes (ONA) and lamina cribosa (LC) cells? Is there a functional cross-talk between ET and nitric oxide (NO)? 2) What signal transduction mechanisms and transcriptional regulation sites are associated with ET synthesis following elevation of pressure, neuronal regulation or activation of the NO pathway in RPE, ONA and LC cells? 3) Does ET play a role in the optic nerve damage observed in the in vivo rat elevated pressure model? Are there changes in ET receptor expression in various ocular tissues following elevation of IOP and is there a correlation between ET aqueous concentrations to elevations in IOP? and 4) Determine the ET receptor subtype involved and the role of NO in the optic nerve damage and effects on axonal transport induced by elevated pressure or ET administration.
These specific aims are designed to determine if ET contributes to the optic neuropathy associated with elevations in IOP. Ultimately these studies could provide insight into the etiology of glaucoma and propose new alternative treatments for patients with glaucoma.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011979-06
Application #
6688231
Study Section
Special Emphasis Panel (ZRG1-SSS-R (02))
Program Officer
Liberman, Ellen S
Project Start
1998-12-01
Project End
2005-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
6
Fiscal Year
2004
Total Cost
$396,340
Indirect Cost
Name
University of North Texas
Department
Other Basic Sciences
Type
Schools of Osteopathy
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
Prasanna, Ganesh; Krishnamoorthy, Raghu; Yorio, Thomas (2011) Endothelin, astrocytes and glaucoma. Exp Eye Res 93:170-7
Narayan, Santosh; Prasanna, Ganesh; Tchedre, Kissaou et al. (2010) Thrombin-induced endothelin-1 synthesis and secretion in retinal pigment epithelial cells is rho kinase dependent. J Ocul Pharmacol Ther 26:389-97
Krishnamoorthy, Raghu R; Rao, Vidhya R; Dauphin, Rachel et al. (2008) Role of the ETB receptor in retinal ganglion cell death in glaucoma. Can J Physiol Pharmacol 86:380-93
Rao, Vidhya R; Krishnamoorthy, Raghu R; Yorio, Thomas (2008) Endothelin-1 mediated regulation of extracellular matrix collagens in cells of human lamina cribrosa. Exp Eye Res 86:886-94
Dibas, Adnan; Yang, Ming-Hui; He, Shaoqing et al. (2008) Changes in ocular aquaporin-4 (AQP4) expression following retinal injury. Mol Vis 14:1770-83
Zhang, Xinyu; Clark, Abbot F; Yorio, Thomas (2008) FK506-binding protein 51 regulates nuclear transport of the glucocorticoid receptor beta and glucocorticoid responsiveness. Invest Ophthalmol Vis Sci 49:1037-47
He, Shaoqing; Dibas, Adnan; Yorio, Thomas et al. (2007) Parallel signaling pathways in endothelin-1-induced proliferation of U373MG astrocytoma cells. Exp Biol Med (Maywood) 232:370-84
He, Shaoqing; Prasanna, Ganesh; Yorio, Thomas (2007) Endothelin-1-mediated signaling in the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in astrocytes. Invest Ophthalmol Vis Sci 48:3737-45
Rao, Vidhya R; Krishnamoorthy, Raghu R; Yorio, Thomas (2007) Endothelin-1, endothelin A and B receptor expression and their pharmacological properties in GFAP negative human lamina cribrosa cells. Exp Eye Res 84:1115-24
Zhang, Xinyu; Clark, Abbot F; Yorio, Thomas (2006) Heat shock protein 90 is an essential molecular chaperone for nuclear transport of glucocorticoid receptor beta. Invest Ophthalmol Vis Sci 47:700-8

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