Glaucoma is a leading cause of visual impairment and blindness in the US and worldwide. However, the molecular mechanisms responsible for the development of glaucoma are poorly understood. The use of anti-inflammatory glucocorticoids (GCs) can cause elevated intraocular pressure (IOP) and glaucoma in susceptible individuals. These """"""""steroid responders"""""""" are at higher risk for developing primary open-angle glaucoma (POAG). Almost all POAG patients are steroid responders. GC-induced ocular hypertension and glaucoma is clinically similar to POAG, and GC effects on the trabecular meshwork (TM), the tissue responsible for regulating aqueous humor outflow (and therefore IOP), mimic many of the molecular and biochemical changes that occur in POAG. Two major isoforms of the glucocorticoid receptor (GR) mediate GC biological responsiveness. GRa is a ligand activated transcription factor and GRb is a dominant negative regulator of GC activities. We recently found that glaucomatous TM (GTM) cells have very low levels of GRb compared to normal TM (NTM) cells, which makes GTM cells much more susceptible to the glaucomatous effects of GCs. Our overall hypothesis is that: (a) high expression of GR?;in normal TM cells leads to GC resistance, and low levels of GR?; expression, as found in GTM, leads to enhanced GC responsiveness and elevated IOP in glaucoma and (b) GR?;activity and expression are regulated by specific splicesome proteins and by translocation to the nucleus via specific importins. The following specific aims will address and test this hypothesis: (1) to investigate whether altered expression and/or activity of splicesome proteins regulate GR?;expression in the TM in the context of glaucoma, (2) to delineate the role of differential trafficking of GR?;and GR?;in regulating GC sensitivity in the normal and glaucomatous TM, and (3) to evaluate whether GC-induced ocular hypertension is regulated by GR?;expression in ex vivo perfusion cultured anterior segments as well as in vivo in mice. This research explores for the first time the roles of alternative splicing and nuclear translocation in the TM, will develop 2 new models of GC-induced ocular hypertension as well as will provide better insights into the pathogenesis of GC-induced ocular hypertension, steroid glaucoma, and POAG.

Public Health Relevance

Glaucoma is a leading cause of visual impairment and world-wide blindness. The use of anti-inflammatory steroids can cause elevated pressure inside eyes leading to glaucoma in susceptible individuals. This steroid response is found in most glaucoma patients and is an important risk factor in the development of glaucoma. We have discovered a likely mechanism responsible for this steroid responsiveness and are evaluating its role in the development of glaucoma.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY016242-06A1
Application #
8236475
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
Project Start
2004-12-01
Project End
2017-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
6
Fiscal Year
2012
Total Cost
$382,688
Indirect Cost
$114,641
Name
University of North Texas
Department
Anatomy/Cell Biology
Type
Other Domestic Higher Education
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
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Dibas, Adnan; Yorio, Thomas (2016) Glucocorticoid therapy and ocular hypertension. Eur J Pharmacol 787:57-71
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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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