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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Chin, Hemin R
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Duke University
Schools of Medicine
United States
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Ge, Pei; Navarro, Iris D; Kessler, Marco M et al. (2016) The Soluble Guanylate Cyclase Stimulator IWP-953 Increases Conventional Outflow Facility in Mouse Eyes. Invest Ophthalmol Vis Sci 57:1317-26
Sherwood, Joseph M; Reina-Torres, Ester; Bertrand, Jacques A et al. (2016) Measurement of Outflow Facility Using iPerfusion. PLoS One 11:e0150694
Paula, Jayter S; O'Brien, Colm; Stamer, W Daniel (2016) Life under pressure: The role of ocular cribriform cells in preventing glaucoma. Exp Eye Res 151:150-9
Braakman, Sietse T; Moore Jr, James E; Ethier, C Ross et al. (2016) Transport across Schlemm's canal endothelium and the blood-aqueous barrier. Exp Eye Res 146:17-21
Elliott, Michael H; Ashpole, Nicole E; Gu, Xiaowu et al. (2016) Caveolin-1 modulates intraocular pressure: implications for caveolae mechanoprotection in glaucoma. Sci Rep 6:37127
Overby, Darryl R; Clark, Abbot F (2015) Animal models of glucocorticoid-induced glaucoma. Exp Eye Res 141:15-22
Boussommier-Calleja, Alexandra; Li, Guorong; Wilson, Amanda et al. (2015) Physical Factors Affecting Outflow Facility Measurements in Mice. Invest Ophthalmol Vis Sci 56:8331-9
Dautriche, Cula N; Szymanski, Dennis; Kerr, Matthew et al. (2015) A biomimetic Schlemm's canal inner wall: A model to study outflow physiology, glaucoma pathology and high-throughput drug screening. Biomaterials 65:86-92
Dismuke, W Michael; Challa, Pratap; Navarro, Iris et al. (2015) Human aqueous humor exosomes. Exp Eye Res 132:73-7
Chang, Jason Y H; Stamer, W Daniel; Bertrand, Jacques et al. (2015) Role of nitric oxide in murine conventional outflow physiology. Am J Physiol Cell Physiol 309:C205-14

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