The cause of the elevated aqueous humor outflow resistance associated with primary open angle glaucoma (POAG) is unknown. Studies aimed at determining the locus of this resistance in both normal and POAG eyes indicate that the bulk of outflow resistance occurs in the immediate vicinity of the inner wall endothelium of Schlemm's canal (SC). Pores found in the inner wall endothelial cells (SC cells) appear important in fluid transport across this endothelium. Our group and others have found that there is a significant reduction of inner wall pore density in POAG eyes. It is likely that these pores are formed in response to cell deformation resulting from the transcellular pressure drop across the inner wall endothelium. If SC cells were to become stiffer, then fewer pores might be expected to form, presumably leading to elevated outflow resistance. Accordingly, we hypothesize that the ocular hypertension characteristic of POAG results from an intro, including magnetic twisting cytometry (MTC), atomic force microscopy (AFM), and a unique embodiment of traction force microscopy called cell mapping rheometry. These studies will allow us to evaluate the stiffness of these cells and the traction forces they can generate. Second, we will investigate the behavior of SC cells on a stretchable gel substrate, and in a microporous filter perfusion system that allows us to grow these cells on a filter and perfuse them in a basal to apical direction (the physiological direction). These studies will examine how SC cells respond to mechanical distension. Third, our studies will focus on the biomechanics of pore formation in these cells and how this process is modulated by SC cell stiffness in enucleated human eyes and in an organ culture system. Fourth, to test the hypothesis that mediators of outflow resistance exert their effects through mechanical events involving changes in SC cell deformation and pore formation, we will use a finite riments, we will compare the biomechanical behavior of normal C cells to those of glaucomatous SC cells. Together, these aims will allow us to definitively determine whether increased stiffness of SC cells leads to a decreased inner wall porosity and consequently the increased outflow resistance characteristic of most cases of POAG.

Public Health Relevance

Most treatments for glaucoma focus on altering the rate of aqueous humor formation or altering the path of aqueous humor outflow, but do not target the diseased tissue responsible for the elevated intraocular pressure characteristic of most cases of glaucoma. These treatments often slow the progression of the disease at the optic nerve, but frequently do not stop it. If we can determine the cause of the elevated pressure, then we may be able to develop a more effective pressure-lowering treatment or cure for this debilitating disease. ????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY019696-03
Application #
8136021
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Agarwal, Neeraj
Project Start
2009-09-30
Project End
2014-09-29
Budget Start
2011-09-30
Budget End
2012-09-29
Support Year
3
Fiscal Year
2011
Total Cost
$786,605
Indirect Cost
Name
Northwestern University at Chicago
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
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
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
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
Williams, Andrew M; Stamer, W Daniel; Allingham, R Rand (2016) Increasing the Availability and Quality of Donor Eyes for Research. JAMA Ophthalmol 134:351-2
Notbohm, Jacob; Banerjee, Shiladitya; Utuje, Kazage J C et al. (2016) Cellular Contraction and Polarization Drive Collective Cellular Motion. Biophys J 110:2729-38
Williams, Andrew M; Perkumas, Kristin M; Perry, Isaac et al. (2016) Successful Implementation of a Program for Increasing Donor Eyes for Research: The Duke-Miracles In Sight Program. J Ocul Pharmacol Ther 32:145-9
Wang, Karin; Cai, Li-Heng; Lan, Bo et al. (2016) Hidden in the mist no more: physical force in cell biology. Nat Methods 13:124-5
Ren, Ruiyi; Li, Guorong; Le, Thuy Duong et al. (2016) Netarsudil Increases Outflow Facility in Human Eyes Through Multiple Mechanisms. Invest Ophthalmol Vis Sci 57:6197-6209

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