Glucocorticoid (GC) administration has been associated with an increase in intraocular pressure (IOP), particularly in patients with primary open-angle glaucoma (POAG) where greater than 90% are considered glucocorticoid responders as compared to 33% of the general population. The reason for this difference in responsiveness among the population is not clear and the molecular mechanism for the hyper-responsiveness among glaucoma patients still remains unknown. It has been reported that the GC receptor beta (GRbeta), primarily located in the nucleus, functions as a dominant negative regulator of the transcriptional activity of GRalpha, possibly forming inactive heterodimers. Such an action is consistent with recent reports that elevated GRbeta is associated with glucocorticoid resistance in asthma patients. Preliminary observations in our laboratory shows that normal trabecular meshwork (TM) cell lines express relatively higher amounts of GRbeta than glaucomatous TM cell lines and that GRbeta is highly concentrated within the nucleus in these normal but not glaucomatous TM cell lines. This suggests a potential role of GRbeta in contributing to glucocorticoid responsiveness in TM cells. It is proposed that decreased nuclear amounts of GRbeta could result in the enhanced transcriptional activity of GRalpha and contribute to glucocorticoid hyper-responsiveness seen in glaucoma patients. Consistent with this hypothesis has been the finding that the peripheral vascular response to GCs is enhanced in patients with POAG. The overall goal of this proposal is to demonstrate that GRbeta is a key component in the regulation of the GC GRalpha response in ocular tissues and the relative expression of GRbeta is important for GC action. The hypothesis to test is that high expression of GRbeta in TM cells leads to GC resistance, and that low levels of GRbeta expression, as found in glaucomatous TM, leads to GC hyper-responsiveness and ocular hypertension.
Four aims are designed to address this hypothesis and include: 1) determine the mRNA, protein expression and subcellular distribution of GC receptors, GRalpha and GRbeta, in normal and glaucomatous TM cell lines and intact tissue; 2) determine if GRbeta expression and overexpression inhibits GC-induced gene expression in TM cells and the increase in GC-induced IOP in isolated perfusion cultured human anterior segments; does GRbeta knockout with siRNA induce hyper responsiveness in normal cells; 3) identify the trafficking mechanism responsible for moving GRbeta from the cytoplasm to the nucleus and determine the role trafficking may have on the accumulation of nuclear GRbeta in normal and glaucomatous TM cells; 4) determine whether polymorphisms in GRbeta splice sites or in the splicesome factor gene SRp30c are associated with glaucoma or with GC-induced ocular hypertension and if in these patients there is a generalized sensitivity to cutaneous vasoconstriction.
These specific aims are designed to determine if GRbeta regulates GC responsiveness and if decreases in its expression contribute to ocular hypertension often seen in patients with POAG.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY016242-03
Application #
7273556
Study Section
Special Emphasis Panel (ZRG1-AED (01))
Program Officer
Liberman, Ellen S
Project Start
2005-09-30
Project End
2010-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
3
Fiscal Year
2007
Total Cost
$370,370
Indirect Cost
Name
University of North Texas
Department
Pharmacology
Type
Other Domestic Higher Education
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
O'Brien, Colm; Clark, Abbot F (2016) Introduction to EER Special Issue on ocular fibrosis. Exp Eye Res 142:1
Stamer, W Daniel; Clark, Abbot F (2016) The many faces of the trabecular meshwork cell. Exp Eye Res :
Dibas, Adnan; Yorio, Thomas (2016) Glucocorticoid therapy and ocular hypertension. Eur J Pharmacol 787:57-71
Overby, Darryl R; Clark, Abbot F (2015) Animal models of glucocorticoid-induced glaucoma. Exp Eye Res 141:15-22
Peters, Joseph C; Bhattacharya, Sanjoy; Clark, Abbot F et al. (2015) Increased Endoplasmic Reticulum Stress in Human Glaucomatous Trabecular Meshwork Cells and Tissues. Invest Ophthalmol Vis Sci 56:3860-8
Pang, Iok-Hou; Millar, J Cameron; Clark, Abbot F (2015) Elevation of intraocular pressure in rodents using viral vectors targeting the trabecular meshwork. Exp Eye Res 141:33-41
Ethier, C Ross; Morrison, John C; Clark, Abbott F (2015) Introduction to special issue on glaucomatous optic neuropathy: In vivo models and techniques. Exp Eye Res 141:1-2
Zode, Gulab S; Sharma, Arti B; Lin, Xiaolei et al. (2014) Ocular-specific ER stress reduction rescues glaucoma in murine glucocorticoid-induced glaucoma. J Clin Invest 124:1956-65
Clark, Abbot F (2014) A useful mouse model of glucocorticoid-induced ocular hypertension. Invest Ophthalmol Vis Sci 55:4934
Jain, Ankur; Wordinger, Robert J; Yorio, Thomas et al. (2014) Role of the alternatively spliced glucocorticoid receptor isoform GRβ in steroid responsiveness and glaucoma. J Ocul Pharmacol Ther 30:121-7

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