The long term goal of our research is to understand the anatomic and biochemical factors that control aqueous outflow resistance in the normal eye, and the pathophysiologic changes that occur in the glaucomatous eye. Our overall hypothesis: In the normal eye, the extracellular matrix (ECM) underlying the cells of Schlemm's canal creates the majority of aqueous outflow resistance, with the canal cells contributing about 22% of the resistance through their interaction with the ECM. This ratio is unknown in POAG. Three hypothesis arise from this, based upon findings from our completed grant, and will be tested in our current proposal: 1) Although the ECM is primarily responsible for aqueous outflow resistance, the ECM is made by trabecular cells, and outflow resistance is ultimately a """"""""cellular"""""""" process. Trabecular cells can respond to stimuli and change their synthetic profile. Two clinical findings will be studied. Both findings involve molecules that induce cellular changes in other tissues. They are prototypes to test if TM cells respond in the same way, and if TM cell changes can affect IOP: (1) TGF-beta2 is increased in the aqueous of POAG eyes. We believe it is the fundamental mechanism for the development of POAG. It causes increased IOP in cultured human eyes, and may be the long-sought model for the pathogenesis of POAG (aim 1). (2) Prostaglandin treatment decreases IOP clinically, and also in cultured eyes. The mechanism of prostaglandins in lowering IOP remains contested: although all studies agree it increases uveoscleral outflow, they disagree on its effect on the TM. We believe PG affect trabecular cells to decrease IOP (aim 2). 2) The small increase of ECM in POAG indicates an """"""""anatomic plug"""""""" is not present. Instead, POAG is a derangement of a physiologic process, best found by comparisons with normal eyes. Both biochemical and structural evidence will test this hypothesis. Myocilin is present in aqueous, and can increase IOP in cultured eyes. Aqueous levels in normal eyes and POAG are unknown. If elevated in POAG, this would be missed by microscopy: not seen as an """"""""anatomic plug"""""""" (aim 3). A change in the cellular properties of the canal cells in glaucoma (""""""""stiffer"""""""" or more adherent cells that resist aqueous outflow) could elevate IOP but would not be seen by microscopy. Removal of Schlemm's canal cells in POAG should determine their contribution to outflow resistance (aim 4). 3) Regions of the TM where Schlemm's canal cells do not sit on ECM (""""""""expanded JCT configuration"""""""") have less outflow resistance due to loss of the canal cell-ECM interaction. This expanded JCT configuration differs significantly from the classic large lumen Schlemm's canal. These regions will be """"""""preferential flow"""""""" regions, and aqueous tracers should appear in these regions first. If this occurs, it would change our basic understanding of how aqueous passes through the TM (aim 5). ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY007065-22
Application #
7452333
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Agarwal, Neeraj
Project Start
1987-07-01
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
22
Fiscal Year
2008
Total Cost
$575,144
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Hann, Cheryl R; Vercnocke, Andrew J; Bentley, Michael D et al. (2014) Anatomic changes in Schlemm's canal and collector channels in normal and primary open-angle glaucoma eyes using low and high perfusion pressures. Invest Ophthalmol Vis Sci 55:5834-41
Kuchtey, John; Chowdhury, Uttio Roy; Uptegraft, Colby C et al. (2013) A de novo MYOC mutation detected in juvenile open angle glaucoma associated with reduced myocilin protein in aqueous humor. Eur J Med Genet 56:292-6
Hann, Cheryl R; Bentley, Michael D; Vercnocke, Andrew et al. (2011) Imaging the aqueous humor outflow pathway in human eyes by three-dimensional micro-computed tomography (3D micro-CT). Exp Eye Res 92:104-11
Lei, Y; Garrahan, N; Hermann, B et al. (2011) Transretinal degeneration in ageing human retina: a multiphoton microscopy analysis. Br J Ophthalmol 95:727-30
Hann, Cheryl R; Fautsch, Michael P (2011) The elastin fiber system between and adjacent to collector channels in the human juxtacanalicular tissue. Invest Ophthalmol Vis Sci 52:45-50
Last, Julie A; Pan, Tingrui; Ding, Yuzhe et al. (2011) Elastic modulus determination of normal and glaucomatous human trabecular meshwork. Invest Ophthalmol Vis Sci 52:2147-52
Howell, Kyle G; Vrabel, Anne M; Chowdhury, Uttio Roy et al. (2010) Myocilin levels in primary open-angle glaucoma and pseudoexfoliation glaucoma human aqueous humor. J Glaucoma 19:569-75
Resch, Zachary T; Hann, Cheryl R; Cook, Kimberly A et al. (2010) Aqueous humor rapidly stimulates myocilin secretion from human trabecular meshwork cells. Exp Eye Res 91:901-8
Chowdhury, Uttio Roy; Madden, Benjamin J; Charlesworth, Mary Christine et al. (2010) Proteome analysis of human aqueous humor. Invest Ophthalmol Vis Sci 51:4921-31
Hann, Cheryl R; Fautsch, Michael P (2009) Preferential fluid flow in the human trabecular meshwork near collector channels. Invest Ophthalmol Vis Sci 50:1692-7

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