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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022634-02
Application #
8549256
Study Section
Special Emphasis Panel (BVS)
Program Officer
Chin, Hemin R
Project Start
2012-09-30
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$388,788
Indirect Cost
$151,288
Name
Boston University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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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 *1-deficient mice: a novel murine model for primary open angle glaucoma. PLoS One 8:e60156
Zhu, Jing-ying; Ye, Wen; Wang, Ti et al. (2013) Reversible changes in aqueous outflow facility, hydrodynamics, and morphology following acute intraocular pressure variation in bovine eyes. Chin Med J (Engl) 126:1451-7
Yang, Chen-Yuan Charlie; Liu, Ye; Lu, Zhaozeng et al. (2013) Effects of Y27632 on aqueous humor outflow facility with changes in hydrodynamic pattern and morphology in human eyes. Invest Ophthalmol Vis Sci 54:5859-70
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