Cataracts are a serious risk to those undergoing steroid therapy, restricting the efficacy of these compounds. Steroid-induced cataracts are posterior subcapsular, frequently occlude the central visual axis and often require early surgical removal. The main action of steroids is via the glucocorticoid receptor (GR) which mediates gene transactivation and transrepression; the role of GR activation in steroid-induced cataract has not received due attention to date. Reduced levels of glutathione (GSH) in the lens are an early event following glucocorticoid administration. GSH synthesis is negatively regulated by GR activation and this effect is reversed by RU486, a potent GR antagonist. Reduction in GSH levels would perturb the cellular redox balance, increasing cell sensitivity to reactive oxygen species (ROS). Oxidants have long been considered to play an important role in cataract development, and in vitro, lens opacification due to steroid administration can be ameliorated with antioxidants. GSH depletion is also an early event in apoptosis. ROS can trigger apoptosis, as can activation of p53, a protein that has recently been shown also to bind to GR. Additionally, the ratio of the pro- and anti-apoptotic members of the Bcl-2 family of proteins is altered by GR activation. Thus a second pathway to steroidinduced cataract may involve 'apoptosis' induction in the lens epithelial cells with consequences for the underlying developing and maturing lens fiber cells. We hypothesize that steroid-induced cataracts are mediated via GR through its effects on gene expression. The following specific aims are proposed: 1). Steroid-mediated gene regulation of redox:
We aim to test the hypothesis that steroid-GR binding leads to GSH depletion through gene transrepression followed by elevation of ROS. Studies will be conducted to determine a). the localization of GR in the lens epithelium, b). the effect of glucocorticoids on Y-GCS expression and on ROS levels in lens epithelial cells, and c). the oxidation of lens proteins following glucocorticoid. treatment of lenses. 2). Steroid-induced (apoptotic) disruption of lens cell development: We will test the hypothesis that steroid-GR binding leads to activation of proteins involved in the intrinsic, mitochondrial, pathway of lapoptosis' in lens epithelial cells which culminates in disturbance of their normal maturation.
| James, Eric R (2007) The etiology of steroid cataract. J Ocul Pharmacol Ther 23:403-20 |
| James, Eric R; Fresco, Victor M; Robertson, Lorie L (2005) Glucocorticoid-induced changes in the global gene expression of lens epithelial cells. J Ocul Pharmacol Ther 21:11-27 |
| James, Eric R (2004) Parasite cryopreservation by vitrification. Cryobiology 49:201-10 |
| James, Eric R; Robertson, Lorie; Ehlert, Erich et al. (2003) Presence of a transcriptionally active glucocorticoid receptor alpha in lens epithelial cells. Invest Ophthalmol Vis Sci 44:5269-76 |
