Glucocorticoid (GC)-induced ocular hypertension (OHT) and glaucoma (GIG) occurs in 30-40% of the general population. The susceptible people are called GC-responders while the others are called non-responders. Although this ocular disease has been studied for decades, there is a fundamental gap in understanding the disease mechanism. Therefore, the long-term goal of this project is to elucidate the pathways and their components in the trabecular meshwork (TM) that mediate GC-induced OHT and GIG. The objective in this application is to determine the key TM genes that are responsible for GC-induced OHT and GIG. The central hypothesis, based on the fact that GIG is genetically determined, is that a select set of genes in the TM is responsible for GC-induced OHT and GIG. The rationale for this study is that the understanding of GIG helps to develop novel GCs with less potential of inducing GIG as well as better therapeutic effects. In addition, the knowledge of GIG will help us to understand primary open angle glaucoma because they share extensive similarities. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) identify the genes that are differentially expressed or regulated in GC-responder and non-responder bovine TM (BTM) cells/tissues;and 2) determine the role of the genes identified (from SA#1) in GC responsiveness and GC-induced OHT. Under the 1st aim, an already constructed bovine anterior segment perfusion culture model will be used to establish/collect BTM cells and tissues from GC-responder and non-responder eyes. By comparison of gene expression profiles between GC-responders and non-responders, the genes that are differentially expressed will be selected as candidates for GIG. Under the 2nd aim, the candidates from SA#1 will be manipulated in BTM cell cultures and perfusion cultured bovine eyes to determine whether they mediate GC-induced biological effects. This project is significant, because it will elucidate the key factors that determine GC-induced OHT and GIG. The approach is innovative, because TM cells/tissues with clearly defined and recorded IOP response to GCs will be used for gene expression profiling. Ultimately, the discovery of these key factors will no doubt help to better understand this vision-threatening disease. They will serve as a guide for further research in the human eye as well as biomarkers for the development of safer GCs.
The project is relevant to public health because the discovery of genes that mediate glucocorticoid-induced glaucoma is ultimately expected to increase understanding of the pathogenesis of this vision-threatening disease, provide biomarkers for disease prediction, and contribute to the development of safer glucocorticoids. Therefore, the proposed research is relevant to the part of NEI's mission that pertains to developing fundamental knowledge with respect to blinding eye diseases.
|Bermudez, Jaclyn Y; Webber, Hannah C; Patel, Gaurang C et al. (2016) HDAC Inhibitor-Mediated Epigenetic Regulation of Glaucoma-Associated TGFÎ²2 in the Trabecular Meshwork. Invest Ophthalmol Vis Sci 57:3698-707|