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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Texas
Anatomy/Cell Biology
Other Domestic Higher Education
Fort Worth
United States
Zip Code
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
Jain, Ankur; Wordinger, Robert J; Yorio, Thomas et al. (2014) Role of the alternatively spliced glucocorticoid receptor isoform GR? in steroid responsiveness and glaucoma. J Ocul Pharmacol Ther 30:121-7
Jain, Ankur; Liu, Xiangyang; Wordinger, Robert J et al. (2013) Effects of thailanstatins on glucocorticoid response in trabecular meshwork and steroid-induced glaucoma. Invest Ophthalmol Vis Sci 54:3137-42
Jain, Ankur; Wordinger, Robert J; Yorio, Thomas et al. (2012) Spliceosome protein (SRp) regulation of glucocorticoid receptor isoforms and glucocorticoid response in human trabecular meshwork cells. Invest Ophthalmol Vis Sci 53:857-66
Mao, Weiming; Tovar-Vidales, Tara; Yorio, Thomas et al. (2011) Perfusion-cultured bovine anterior segments as an ex vivo model for studying glucocorticoid-induced ocular hypertension and glaucoma. Invest Ophthalmol Vis Sci 52:8068-75
Fingert, John H; Alward, Wallace L; Wang, Kai et al. (2010) Assessment of SNPs associated with the human glucocorticoid receptor in primary open-angle glaucoma and steroid responders. Mol Vis 16:596-601
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
Zhang, Xinyu; Ognibene, Cherie M; Clark, Abbot F et al. (2007) Dexamethasone inhibition of trabecular meshwork cell phagocytosis and its modulation by glucocorticoid receptor beta. Exp Eye Res 84:275-84
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
Zhang, Xinyu; Clark, Abbot F; Yorio, Thomas (2005) Regulation of glucocorticoid responsiveness in glaucomatous trabecular meshwork cells by glucocorticoid receptor-beta. Invest Ophthalmol Vis Sci 46:4607-16