Glaucoma is a leading cause of blindness worldwide. A primary risk factor for the development and progression of primary open-angle glaucoma (POAG) is elevation of the intraocular pressure (IOP), resulting from a rise in aqueous humor outflow resistance. To date, the cause of this elevated resistance in POAG remains unknown. Previous studies have shown that the majority of aqueous outflow resistance is localized near the inner wall endothelium of Schlemm's canal (SC) and the juxtacanalicular connective tissue (JCT). Giant vacuoles and pores, which are characteristic features of the endothelial cells of SC, have long been suspected to play a role in regulating outflow resistance. A significant reduction in the number of giant vacuoles and pores was found in POAG eyes. Abnormal accumulations of extracellular matrix (ECM) within the JCT were also found contributing to resistance in POAG, but their contribution to total outflow resistance remains unknown. Our long-term goal is to determine the mechanisms that regulate outflow resistance in normal eyes and how this is increased in POAG. One obstacle in studying outflow resistance is finding a parameter that can be applied to various species regardless of their outflow anatomy. Our group has recently found, in mouse, bovine, monkey and human eyes, that only a fraction of outflow pathways actively contribute to drainage and termed those areas of outflow as the effective filtration area (EFA). We have demonstrated that EFA increases with higher outflow facility after use of a Rho-kinase inhibitor and decreases after acute and chronic elevation of IOP in bovine, monkey and human eyes. Moreover, we found an inverse relationship between IOP and EFA using a hypotensive mouse model. These results suggest that EFA serves as a valuable indicator across varied species for outflow resistance and IOP. We developed a novel fluorophore guided imaging technique to increase our chances of identifying important morphological and cellular differences between areas with high and low flow that contribute to increased outflow resistance and the pathogenesis of POAG. Additionally, we are now able to view giant vacuole formations of SC endothelial cells in real time using a novel three- dimensional cell culture device. With these two novel approaches, we will test our hypothesis that interactions between SC endothelial cells and their underlying ECM modulate giant vacuole and pore formations, thereby regulating EFA and outflow resistance.
Our specific aims are too;1) Evaluate the inverse relationship between the EFA and IOP in ocular hypertensive animal models;2) Define the inverse relationship between the EFA and the outflow resistance in normal and POAG human eyes and determine the role of SC endothelial cells and their underlying ECM in regulating EFA;3) Determine the mechanisms by which SC endothelial cells and their underlying ECM regulate the outflow using a novel three-dimensional cell culture device with real-time imaging. The results of this study will provide new insights for a novel therapeutic strategy to lower IOP by targeting the trabecular meshwork, where the initial problem resides.
Primary open angle glaucoma is a leading form of blindness worldwide, but the cause of this disease remains unclear. Elevation of the intraocular pressure is a primary risk factor for the development and progression of this disease. The goal of our proposed study is to identify the key factors that contribute to the elevation of intraocular pressure in primary open angle glaucoma, and the results of our research will provide new knowledge for developing novel therapeutic strategies.
| Raghunathan, VijayKrishna; Eaton, J Seth; Christian, Brian J et al. (2017) Biomechanical, ultrastructural, and electrophysiological characterization of the non-human primate experimental glaucoma model. Sci Rep 7:14329 |
| Ren, Ruiyi; Li, Guorong; Le, Thuy Duong et al. (2016) Netarsudil Increases Outflow Facility in Human Eyes Through Multiple Mechanisms. Invest Ophthalmol Vis Sci 57:6197-6209 |
| Cha, Elliott D K; Xu, Jia; Gong, Lihua et al. (2016) Variations in active outflow along the trabecular outflow pathway. Exp Eye Res 146:354-60 |
| Swain, David L; Ho, Joseph; Lai, Julia et al. (2015) Shorter scleral spur in eyes with primary open-angle glaucoma. Invest Ophthalmol Vis Sci 56:1638-48 |
| Pizzirani, Stefano; Gong, Haiyan (2015) Functional Anatomy of the Outflow Facilities. Vet Clin North Am Small Anim Pract 45:1101-26, v |
| Vargas-Pinto, Rocio; Lai, Julia; Gong, Haiyan et al. (2015) Finite element analysis of the pressure-induced deformation of Schlemm's canal endothelial cells. Biomech Model Mechanobiol 14:851-63 |
| Yang, Chen-Yuan Charlie; Huynh, Tiffany; Johnson, Mark et al. (2014) Endothelial glycocalyx layer in the aqueous outflow pathway of bovine and human eyes. Exp Eye Res 128:27-33 |
| Gong, Haiyan; Yang, Chen-Yuan Charlie (2014) Morphological and hydrodynamic correlations with increasing outflow facility by rho-kinase inhibitor Y-27632. J Ocul Pharmacol Ther 30:143-53 |
| Buys, Emmanuel S; Ko, Yu-Chieh; Alt, Clemens et al. (2013) Soluble Guanylate Cyclase a1-Deficient Mice: a novel murine model for Primary Open Angle Glaucoma. Ann Neurosci 20:65-6 |
| Swaminathan, Swarup S; Oh, Dong-Jin; Kang, Min Hyung et al. (2013) Secreted protein acidic and rich in cysteine (SPARC)-null mice exhibit more uniform outflow. Invest Ophthalmol Vis Sci 54:2035-47 |
Showing the most recent 10 out of 14 publications
