Molecular mechanisms in steroid-induced glaucoma.

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Glucocorticosteroids are known to cause intraocular pressure (IOP) elevation in humans. This induced ocular hypertension can lead to glaucomatous visual loss. Steroid-induced glaucoma has over the past few years become more prevalent as many posterior pole conditions are increasingly been treated with potent, long-lasting steroid preparations. Steroid-induced open angle glaucoma is caused by a decrease of trabecular meshwork (TM) outflow facility. Cellular and molecular mechanisms underlying this decrease in outflow facility have been studied in tissue and/or organ culture. However, despite significant advances to our understanding of this disease, we still do not fully understand the molecular mechanisms that lead to steroid induced decrease in facility and the resulting IOP elevation. Over the past few years we have developed two animal models (bovine and ovine) for the study of steroid-induced glaucoma in-vivo and have used one of them to gain some insight into the pathogenesis of the disease. In this project we propose to use the ovine steroid-induced IOP elevation model to dissect the molecular mechanisms of this disease. Our overall hypothesis is that steroid-induced changes of gene and protein expression in the trabecular meshwork (TM) lead to changes in the outflow pathways which ultimately cause a reduction in outflow facility and IOP elevation. We thus propose the following specific aims: 1. To define the role of key genes in a number of inter-connecting networks in steroid induced IOP elevation. Our hypothesis is that these closely linked gene networks mediate the steroid-induced changes in facility and IOP. Thus specific perturbation of these networks will ameliorate or prevent the development of steroid- induced IOP elevation. 2. To study the time-course of gene expression changes that occur in the TM during the development of steroid-induced IOP elevation. Our hypothesis predicts that a small set of genes that belong to a limited number of networks are the initial response to steroid therapy and that changes in their expression ultimately causes changes in the trabecular meshwork that lead to a reduction in outflow facility and IOP elevation. 3. To detect (by proteomic analysis) protein changes that occur during the development of steroid-induced IOP elevation. Our hypothesis is that post-translational modifications (like phosphorylation or glycosylation) modify the activity of key molecules in pathways that affect the development of steroid-induced IOP elevation and the onset of glaucoma. This project is expected to define targets for pharmacologic intervention in steroid-induced glaucoma. In addition, and because of the similarities of steroid-induced with chronic open angle glaucoma, we expect that knowledge gained during this project will help to elucidate some of the pathophysiology of the latter condition as well.