Results from clinical trials demonstrate that significant, sustained intraocular pressure (IOP) reduction in people with glaucoma slows or halts vision loss, even in patients with low-tension glaucoma. While the etiology of ocular hypertension in glaucoma is known to involve the conventional drainage pathway, the cellular mechanisms responsible for generation of this extra resistance are unknown. It seems likely that the homeostatic mechanisms that regulate IOP in people with ocular hypertension are defective and may be similar to those involved in the regulation of systemic blood pressure, including those that regulate vascular tone. A key signaling molecule for local regulation of vascular tone is nitric oxide (NO), a free radical produced in vascular endothelia by endothelial NO synthase (eNOS). Our central hypothesis, supported by strong preliminary data, is that IOP-dependent shear stress within Schlemm's canal (SC) is a key player within a dynamic endogenous signaling system ("feedback loop") that regulates conventional outflow resistance through NO production. In some glaucomatous individuals, this shear stress-NO system may be compromised, leading ultimately to increased outflow resistance and elevated IOP. The goal of the present proposal is to test this hypothesis by careful examination of the effect of elevated IOP and shear stress in SC and establish the determinants of, and the time course for, NO production by SC cells (aim 1). Consequences of shear and NO production on SC monolayer permeability and trabecular meshwork cell contractility (and flow patterns through the trabecular meshwork) are looked at independently in aim 2 and aim 3, respectively. Results obtained from these investigations will provide a basic understanding of the role of NO in aqueous outflow resistance regulation, uncover novel therapeutic targets for glaucoma therapy and generate a foundation for future investigations.

Public Health Relevance

Glaucoma is treatable. Data from large clinical trials demonstrate that lowering intraocular pressure in people with glaucoma, whether intraocular pressure is elevated or not, slows or stops vision loss. Unfortunately, current medical therapies do not lower intraocular pressure sufficiently in most, and do not target the primary outflow pathway. The present proposal examines a novel pressure-sensitive mechanism involving nitric oxide production that appears to regulate the movement of aqueous humor out through the primary outflow pathway, the chief determinant of intraocular pressure. Improved understanding of this pathway is expected to identify a new group of druggable targets for intraocular pressure control.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022359-03
Application #
8634103
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Chin, Hemin R
Project Start
2012-04-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
$300,719
Indirect Cost
$73,163
Name
Duke University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Stamer, W Daniel; Braakman, Sietse T; Zhou, Enhua H et al. (2015) Biomechanics of Schlemm's canal endothelium and intraocular pressure reduction. Prog Retin Eye Res 44:86-98
Overby, Darryl R; Bertrand, Jacques; Schicht, Martin et al. (2014) The structure of the trabecular meshwork, its connections to the ciliary muscle, and the effect of pilocarpine on outflow facility in mice. Invest Ophthalmol Vis Sci 55:3727-36
Li, Guorong; Farsiu, Sina; Chiu, Stephanie J et al. (2014) Pilocarpine-induced dilation of Schlemm's canal and prevention of lumen collapse at elevated intraocular pressures in living mice visualized by OCT. Invest Ophthalmol Vis Sci 55:3737-46
Dismuke, W Michael; Liang, Jin; Overby, Darryl R et al. (2014) Concentration-related effects of nitric oxide and endothelin-1 on human trabecular meshwork cell contractility. Exp Eye Res 120:28-35
Lei, Yuan; Stamer, William D; Wu, Jihong et al. (2014) Cell senescence reduced the mechanotransduction sensitivity of porcine angular aqueous plexus cells to elevation of pressure. Invest Ophthalmol Vis Sci 55:2324-8
Overby, Darryl R; Bertrand, Jacques; Tektas, Ozan-YĆ¼ksel et al. (2014) Ultrastructural changes associated with dexamethasone-induced ocular hypertension in mice. Invest Ophthalmol Vis Sci 55:4922-33
Rogers, Morgan E; Navarro, Iris D; Perkumas, Kristin M et al. (2013) Pigment epithelium-derived factor decreases outflow facility. Invest Ophthalmol Vis Sci 54:6655-61
Li, G; Gonzalez, P; Camras, L J et al. (2013) Optimizing gene transfer to conventional outflow cells in living mouse eyes. Exp Eye Res 109:8-16
Lei, Yuan; Stamer, William D; Wu, Jihong et al. (2013) Oxidative stress impact on barrier function of porcine angular aqueous plexus cell monolayers. Invest Ophthalmol Vis Sci 54:4827-35