In primary open-angle glaucoma (POAG), elevated intraocular pressure (IOP) is often attributed to diminished aqueous humor (AH) outflow facility caused by accumulation of extracellular matrix material (ECM) in the juxtacanicular region of the trabecular meshwork (TM). A balance normally exists between ECM deposition and degradation within the normal human TM. Factors that shift the balance towards either ECM deposition or inhibition of ECM degradation results in accumulation of ECM. Recent reports indicate that transforming growth factor-22 (TGF-22) is involved in the pathogenesis of POAG. TGF-22 is elevated in the AH of patients with POAG. In addition, using both cultured TM cells and a perfused anterior eye organ culture model (POC), TGF-22 increased synthesis and deposition of ECM proteins. However, the biological actions of most growth factors are often counterbalanced by other growth factors. Preliminary published data from our laboratory indicates that (a) BMP-4 inhibits TGF-22 stimulation of fibronectin (FN) and plasminogen activator inhibitor-1 (PAI-1) secretion by cultured TM cells and (b) gremlin, a BMP antagonist is upregulated in multiple glaucomatous TM cell lines. In addition new preliminary data indicates that gremlin is present in human AH and TM tissues. We hypothesize that (a) BMPs inhibit TGF-22 stimulation of ECM-related protein secretion by TM cells and (b) gremlin blocks the inhibitory action of BMPs resulting in increased outflow resistance and elevated IOP. The following specific aims have been developed to test the hypothesis: (1) demonstrate that TGF-22 upregulates the synthesis and secretion of ECM-related proteins by TM cells and this upregulation is inhibited by BMP-4, (2) determine the signaling pathway used by BMPs to block TGF-22 upregulation of ECM-related proteins in TM cells;(3) utilize (a) the POC model to demonstrate that BMPs block the stimulatory effect of TGF-22 on both secretion of ECM proteins and elevation of IOP and (b) utilize both the POC model and mouse in vivo experiments to demonstrate that inhibition of BMP via gremlin results in increased outflow resistance and elevated IOP due to accumulation of ECM proteins. This study is unique because it will address the relationships between TGF-22 and BMPs in the pathogenesis of glaucoma as well as the role of the BMP antagonist gremlin in the human TM. Public health relevance includes our ability to identify new targets for the treatment of glaucoma.

Public Health Relevance

. Glaucoma is a leading cause of blindness in the United States and is caused by elevated pressure in the eye. Elevated eye pressure is a result of a resistance to the exit of fluid from the front of the eye. This study is relevant because it will examine the role of local growth factors in the control of eye pressure and may lead to new treatments for glaucoma.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY017374-05
Application #
8247078
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
Project Start
2008-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$391,242
Indirect Cost
$118,548
Name
University of North Texas
Department
Anatomy/Cell Biology
Type
Other Domestic Higher Education
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
Wordinger, Robert J; Clark, Abbot F (2014) Lysyl oxidases in the trabecular meshwork. J Glaucoma 23:S55-8
Sethi, Anirudh; Wordinger, Robert J; Clark, Abbot F (2013) Gremlin utilizes canonical and non-canonical TGF* signaling to induce lysyl oxidase (LOX) genes in human trabecular meshwork cells. Exp Eye Res 113:117-27
Medina-Ortiz, Wanda E; Belmares, Ricardo; Neubauer, Sandra et al. (2013) Cellular fibronectin expression in human trabecular meshwork and induction by transforming growth factor-*2. Invest Ophthalmol Vis Sci 54:6779-88
McDowell, Colleen M; Tebow, Holly E; Wordinger, Robert J et al. (2013) Smad3 is necessary for transforming growth factor-beta2 induced ocular hypertension in mice. Exp Eye Res 116:419-23
Sethi, Anirudh; Mao, Weiming; Wordinger, Robert J et al. (2011) Transforming growth factor-beta induces extracellular matrix protein cross-linking lysyl oxidase (LOX) genes in human trabecular meshwork cells. Invest Ophthalmol Vis Sci 52:5240-50
Tovar-Vidales, Tara; Clark, Abbot F; Wordinger, Robert J (2011) Focus on molecules: transglutaminase 2. Exp Eye Res 93:2-3
Sethi, Anirudh; Jain, Ankur; Zode, Gulab S et al. (2011) Role of TGFbeta/Smad signaling in gremlin induction of human trabecular meshwork extracellular matrix proteins. Invest Ophthalmol Vis Sci 52:5251-9
Tovar-Vidales, Tara; Roque, Rouel; Clark, Abbot F et al. (2008) Tissue transglutaminase expression and activity in normal and glaucomatous human trabecular meshwork cells and tissues. Invest Ophthalmol Vis Sci 49:622-8
Wordinger, Robert J; Zode, Gulab; Clark, Abbot F (2008) Focus on molecules: gremlin. Exp Eye Res 87:78-9