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
Chandrawati, Rona; Chang, Jason Y H; Reina-Torres, Ester et al. (2017) Localized and Controlled Delivery of Nitric Oxide to the Conventional Outflow Pathway via Enzyme Biocatalysis: Toward Therapy for Glaucoma. Adv Mater 29:
Tam, Lawrence C S; Reina-Torres, Ester; Sherwood, Joseph M et al. (2017) Enhancement of Outflow Facility in the Murine Eye by Targeting Selected Tight-Junctions of Schlemm's Canal Endothelia. Sci Rep 7:40717
O'Callaghan, Jeffrey; Crosbie, Darragh E; Cassidy, Paul S et al. (2017) Therapeutic potential of AAV-mediated MMP-3 secretion from corneal endothelium in treating glaucoma. Hum Mol Genet 26:1230-1246
Klingeborn, Mikael; Dismuke, W Michael; Bowes Rickman, Catherine et al. (2017) Roles of exosomes in the normal and diseased eye. Prog Retin Eye Res 59:158-177
Madekurozwa, Michael; Reina-Torres, Ester; Overby, Darryl R et al. (2017) Direct measurement of pressure-independent aqueous humour flow using iPerfusion. Exp Eye Res 162:129-138
Klingeborn, Mikael; Dismuke, W Michael; Skiba, Nikolai P et al. (2017) Directional Exosome Proteomes Reflect Polarity-Specific Functions in Retinal Pigmented Epithelium Monolayers. Sci Rep 7:4901
Reina-Torres, Ester; Wen, Joanne C; Liu, Katy C et al. (2017) VEGF as a Paracrine Regulator of Conventional Outflow Facility. Invest Ophthalmol Vis Sci 58:1899-1908
Fini, M Elizabeth; Schwartz, Stephen G; Gao, Xiaoyi et al. (2017) Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine. Prog Retin Eye Res 56:58-83
Chang, Jason Y H; Chow, Lesley W; Dismuke, W Michael et al. (2017) Peptide-Functionalized Fluorescent Particles for In Situ Detection of Nitric Oxide via Peroxynitrite-Mediated Nitration. Adv Healthc Mater 6:
Wen, Joanne C; Reina-Torres, Ester; Sherwood, Joseph M et al. (2017) Intravitreal Anti-VEGF Injections Reduce Aqueous Outflow Facility in Patients With Neovascular Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci 58:1893-1898

Showing the most recent 10 out of 33 publications