Glaucoma is an optic neuropathy which causes irreversible blindness. Our approach to study glaucoma consists of selecting a well-established clinical condition associated with the disease and investigating the clinical parameter at the molecular level. Elevated intraocular pressure (IOP) is the major risk factor for the development of glaucoma. In humans, 90% of the aqueous humor exits the eye through the trabecular meshwork (TM). Thus, a dysfunctional TM results in increased resistance and elevated IOP. Because the physiology of a tissue is governed by the expression of its genes, during the previous grant cycle we examined TM differential expression under conditions of elevated IOP. After analyzing many chip arrays comparing normal and high IOP perfused post-mortem human eyes, we unraveled a number of genes involved in calcification processes. We further uncovered that such processes were not only present in the TM, but also that they seemed to be more active in TMs from glaucomatous patients. Based on these findings, we hypothesize that TM calcification is linked to regulation of IOP and outflow facility. That genes and mechanisms that govern physiological and pathological calcification in the bone and vascular tissues are active in the TM, and that these processes, as well as efforts to inhibit them, are part of the regulatory systems that control aqueous humor outflow. We further hypothesize that failure to maintain TM mineralization in check will affect deposited collagen and elastin cross-linking with deleterious consequences to ECM hardening. To test these hypotheses we propose to further characterize the identified mechanism through three new avenues. The first will investigate the phenomenon in vivo, through the use of transgenic mice. The second will investigate the process in human organ cultures. The third will use primary human TM cells to determine the involvement of two pathways (WNT and LOX-related elastin/collagen cross-linking) in TM mineralization. These two pathways have been independently associated with vascular calcification and osteoblastic differentiation and, with conditions affecting TM function. Results to be obtained with the development of these hypotheses will provide new understanding on the mechanisms regulating outflow resistance and would potentially lead to new treatments for glaucoma.

Public Health Relevance

Glaucoma is the second leading cause of irreversible blindness and the most common cause among African- Americans. Currently, there is no cure for glaucoma. Elevated intraocular pressure (IOP) is the major risk factor for the developing of glaucoma. IOP is maintained by the resistance of the trabecular meshwork to the flow of aqueous humor. The goal of our project is to investigate the relevance of a previously undescribed process of mineralization occurring in the trabecular meshwork for the regulation of IOP. The trabecular meshwork needs to have in place molecular mechanisms that would maintain the physical properties of elasticity, tension and softness. Maintenance of the softness is of highest relevance to the trabecular meshwork's function. Pathological calcification occurs in soft tissues and has important clinical implications. Ectopic calcifications are well known to occur in cardiovascular diseases, atherosclerosis, arthritis, kidney disease and cancers. Vascular calcification decreases elasticity of the blood vessels and increases their brittleness, leading to increase risk of arterial rupture. In this project we aim to characterize this process in the eye of transgenic animals, human eyes from post-mortem donors and primary trabecular meshwork cells obtained from residual tissue after corneal transplants. We will aim to further study the role of inhibitors of calcification in the trabecular meshwork and ultimate open a new door for the development of new treatments for Glaucoma.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013126-13
Application #
8249088
Study Section
Special Emphasis Panel (ZRG1-ETTN-E (92))
Program Officer
Chin, Hemin R
Project Start
2000-08-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
13
Fiscal Year
2012
Total Cost
$460,591
Indirect Cost
$149,381
Name
University of North Carolina Chapel Hill
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Borrás, Terete (2014) The cellular and molecular biology of the iris, an overlooked tissue: the iris and pseudoexfoliation glaucoma. J Glaucoma 23:S39-42
Borrás, Teresa (2014) The effects of myocilin expression on functionally relevant trabecular meshwork genes: a mini-review. J Ocul Pharmacol Ther 30:202-12
Buie, Lakisha K; Karim, Md Zahidul; Smith, Matthew H et al. (2013) Development of a model of elevated intraocular pressure in rats by gene transfer of bone morphogenetic protein 2. Invest Ophthalmol Vis Sci 54:5441-55
Beazley, Kelly E; Lima, Florence; Borras, Teresa et al. (2013) Attenuation of chondrogenic transformation in vascular smooth muscle by dietary quercetin in the MGP-deficient mouse model. PLoS One 8:e76210
Comes, Nuria; Buie, Lakisha K; Borras, Teresa (2011) Evidence for a role of angiopoietin-like 7 (ANGPTL7) in extracellular matrix formation of the human trabecular meshwork: implications for glaucoma. Genes Cells 16:243-59
Spiga, Maria-Grazia; Borras, Teresa (2010) Development of a gene therapy virus with a glucocorticoid-inducible MMP1 for the treatment of steroid glaucoma. Invest Ophthalmol Vis Sci 51:3029-41
Gerometta, Rosana; Spiga, Maria-Grazia; Borras, Teresa et al. (2010) Treatment of sheep steroid-induced ocular hypertension with a glucocorticoid-inducible MMP1 gene therapy virus. Invest Ophthalmol Vis Sci 51:3042-8
Buie, LaKisha K; Rasmussen, Carol A; Porterfield, Eric C et al. (2010) Self-complementary AAV virus (scAAV) safe and long-term gene transfer in the trabecular meshwork of living rats and monkeys. Invest Ophthalmol Vis Sci 51:236-48
Borras, Teresa; Comes, Nuria (2009) Evidence for a calcification process in the trabecular meshwork. Exp Eye Res 88:738-46
Comes, Nuria; Borras, Teresa (2009) Individual molecular response to elevated intraocular pressure in perfused postmortem human eyes. Physiol Genomics 38:205-25

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