The overall goal is to determine the principle site of increased aqueous outflow resistance in primary open-angle glaucoma (POAG), a leading cause of blindness in the USA. As part of these studies, the applicant will evaluate how outflow resistance is generated in the normal human eye. It is conventionally believed that the JCT immediately underlying Schlemm's canal is responsible for the bulk of outflow resistance in the normal eye, and that changes in the extracellular matrix (ECM) in this region lead to glaucoma. However, there has been no direct proof of this proposition. Using quick-freeze/deep-etch morphological techniques, this group has now shown that the ECM in the JCT is more extensive than previously recognized, and can likely generate a significant fraction of aqueous outflow resistance in the normal human eye. An important aspect of this application is to use similar advanced morphological/morphometric techniques to determine whether the outflow resistance of the JCT is increased in POAG. This group and others have also shown that specific plasma-derived proteins can affect aqueous outflow resistance. They hypothesize that these proteins interact with the ECM in the JCT, leading to the extensive ultrastructural network seen using the quick-freeze/deep-etch techniques, and that POAG may result from excessive accumulation of these proteins in the JCT. The applicant will test this hypothesis, and will also examine other macromolecules found in the normal and glaucomatous JCT tissues, as viewed by quick-freeze/deep-etch. While their studies have implicated the JCT as responsible for generating the bulk of aqueous outflow resistance, they have also identified two types of pores in the inner wall of Schlemm's canal that may modulate juxtacanalicular flow resistance. In addition to changes in the JCT, glaucoma might be in part due to changes in one or both of these populations of inner wall pores. In this application, this possibility will be investigated. Exploiting the combined expertise in the areas of hydrodynamics, modeling, physiology, and ultrastructural and immunohistochemical methods, the studies proposed herein could significantly improve understanding of aqueous outflow resistance and its elevation in POAG.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY009699-06
Application #
2856915
Study Section
Visual Sciences C Study Section (VISC)
Project Start
1993-03-01
Project End
1999-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Vargas-Pinto, Rocio; Lai, Julia; Gong, Haiyan et al. (2015) Finite element analysis of the pressure-induced deformation of Schlemm's canal endothelial cells. Biomech Model Mechanobiol 14:851-63
Freddo, Thomas F (2013) A contemporary concept of the blood-aqueous barrier. Prog Retin Eye Res 32:181-95
Zeng, Dehong; Juzkiw, Taras; Read, A Thomas et al. (2010) Young's modulus of elasticity of Schlemm's canal endothelial cells. Biomech Model Mechanobiol 9:19-33
Johnson, Mark; Caro, Nathan; Huang, Jiahn-Dar (2010) Adequacy of exchanging the content of the anterior chamber. Exp Eye Res 91:876-80
Overby, Darryl R; Stamer, W Daniel; Johnson, Mark (2009) The changing paradigm of outflow resistance generation: towards synergistic models of the JCT and inner wall endothelium. Exp Eye Res 88:656-70
Gong, Haiyan; Freddo, Thomas F (2009) The washout phenomenon in aqueous outflow--why does it matter? Exp Eye Res 88:729-37
Freddo, Thomas F; Gong, Haiyan (2009) ETIOLOGY OF IOP ELEVATION IN PRIMARY OPEN ANGLE GLAUCOMA. Optom Glaucoma Soc E J 4:
Lu, Zhaozeng; Overby, Darryl R; Scott, Patrick A et al. (2008) The mechanism of increasing outflow facility by rho-kinase inhibition with Y-27632 in bovine eyes. Exp Eye Res 86:271-81
Scott, Patrick A; Overby, Darryl R; Freddo, Thomas F et al. (2007) Comparative studies between species that do and do not exhibit the washout effect. Exp Eye Res 84:435-43
Johnson, Mark (2006) 'What controls aqueous humour outflow resistance?'. Exp Eye Res 82:545-57

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