Recent clinical trials demonstrate that significant, sustained intraocular pressure reduction in people with glaucoma slows or halts vision loss, even in patients with low-tension glaucoma. While the site of increased resistance in glaucoma is likely located in the conventional drainage pathway, the cellular mechanisms responsible for generation of this extra resistance are unknown. Previous work points to two possibilities that are not mutually exclusive: (i) abnormal accumulation and/or alterations in the extracellular matrix materials of the juxtacanalicular tissue;or (ii) alterations in the function of the intercellular junctions (and associated border pores) of the inner wall of Schlemm's canal. In the present application, we propose to study a family of cell-cell adhesion molecules, the cadherins, in the endothelial cells of Schlemm's canal. Cadherins form adherens junctional complexes, which are present in the conventional drainage pathway, but have only been described morphologically. Since homophilic protein- protein interactions of cadherin extracellular domains on adjacent cells are critical to the formation and maintenance of the integrity of at least three intercellular junctional complexes (including adherens, occludens and gap), and published evidence suggests that cell-cell adhesion plays a role in determining outflow resistance, we hypothesize that cadherins between Schlemm's canal endothelia strongly influence the generation of outflow resistance. Our study will examine cadherins at the molecular and functional levels and (i) specifically target cadherin-5 (plus associated catenin proteins) and disrupt adhesion between Schlemm's canal endothelia;(ii)analyze effects of pressure differences/stretch on relative expression levels, subcellular distribution and phosphorylation status of cadherin-5 plus associated catenins;and (iii) monitor signaling proteins that regulate the formation and remodeling of the cadherin-5 junction complex. Results obtained from these investigations will provide a basic understanding of the role of cadherin proteins in aqueous outflow resistance and uncover novel therapeutic targets for glaucoma therapy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY017007-05
Application #
7761661
Study Section
Special Emphasis Panel (ZRG1-BDCN-A (03))
Program Officer
Agarwal, Neeraj
Project Start
2006-02-02
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2012-01-31
Support Year
5
Fiscal Year
2010
Total Cost
$335,621
Indirect Cost
Name
University of Arizona
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Stamer, W Daniel; Acott, Ted S (2012) Current understanding of conventional outflow dysfunction in glaucoma. Curr Opin Ophthalmol 23:135-43
Zhou, E H; Krishnan, R; Stamer, W D et al. (2012) Mechanical responsiveness of the endothelial cell of Schlemm's canal: scope, variability and its potential role in controlling aqueous humour outflow. J R Soc Interface 9:1144-55
Li, Ang; Leung, Chi Ting; Peterson-Yantorno, Kim et al. (2012) Mechanisms of ATP release by human trabecular meshwork cells, the enabling step in purinergic regulation of aqueous humor outflow. J Cell Physiol 227:172-82
Boussommier-Calleja, Alexandra; Bertrand, Jacques; Woodward, David F et al. (2012) Pharmacologic manipulation of conventional outflow facility in ex vivo mouse eyes. Invest Ophthalmol Vis Sci 53:5838-45
Perkumas, K M; Stamer, W D (2012) Protein markers and differentiation in culture for Schlemm's canal endothelial cells. Exp Eye Res 96:82-7
Pedrigi, Ryan M; Simon, David; Reed, Ashley et al. (2011) A model of giant vacuole dynamics in human Schlemm's canal endothelial cells. Exp Eye Res 92:57-66
VanderWyst, Saumya S; Perkumas, Kristin M; Read, A Thomas et al. (2011) Structural basement membrane components and corresponding integrins in Schlemm's canal endothelia. Mol Vis 17:199-209
Li, Ang; Leung, Chi Ting; Peterson-Yantorno, Kim et al. (2011) Cytoskeletal dependence of adenosine triphosphate release by human trabecular meshwork cells. Invest Ophthalmol Vis Sci 52:7996-8005
Lei, Yuan; Overby, Darryl R; Boussommier-Calleja, Alexandra et al. (2011) Outflow physiology of the mouse eye: pressure dependence and washout. Invest Ophthalmol Vis Sci 52:1865-71
Stamer, W Daniel; Lei, Yuan; Boussommier-Calleja, Alexandra et al. (2011) eNOS, a pressure-dependent regulator of intraocular pressure. Invest Ophthalmol Vis Sci 52:9438-44

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