Glucocorticoids, ocular hypertension, and glaucoma

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DESCRIPTION (provided by applicant): 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.