During the progression of glaucoma, the retinal ganglion cells (RGC) and their axons degenerate. An important target to this damage occurs in the optic nerve head (ONH), where the RGC axons leave the globe to form the optic nerve. Although RGC axonal damage can be caused by different type of insults, it is well- established that elevated intraocular pressure (IOP) and stiffness in the peripapillary region (ppSC) are major contributors to this degeneration. It would seem logical to think that some kind of molecular regulation coordinating the anterior and posterior affected tissues would be of great benefit for a potential treatment of glaucoma. Previously, we had identified Matrix Gla (MGP) as one of most highly expressed genes in the human TM. We had also found that MGP was altered in the TM by elevated IOP, TGF? and dexamethasone, and that calcification markers were increased in TM tissues from glaucoma patients and Mgp-KO mice. The gene transfer of a calcification inducer (BMP2) to the rat?s TM also elicited elevated IOP. Matrix Gla is a potent mineralization inhibitor secreted by cartilage chondrocytes and arteries? vascular smooth muscle cells. Mgp KO mice die at 5-6 weeks due to massive arterial calcification. Arterial calcification results in arterial stiffness and higher systolic blood pressure. In order to investigate the abundance of Mgp in the eye and its contribution to a potential regulation of stiffness in glaucoma in a living animal, we used mouse genetics. To determine the Mgp spatial/ temporal expression in the eye, we generated an Mgp-Cre Knock-in (KI) mouse, containing Mgp DNA fused to an IRES-Cre-cassette. Crosses of this mouse with R26R-floxed reporters (lacZ and td.Tomato) revealed, as expected, Mgp?s high specific expression in the TM region, but also, and surprisingly, Mgp was highly and specifically expressed in the sclera, in particularly the ppSC. Based on these findings, we propose that MGP and its anti-calcification/ anti-stiffness function represents a sole mechanism that affects the source of two basic glaucomatous causes, elevated IOP and ONH damage. Thus, we hypothesize that MGP is a master key-mediator that prevents the occurrence of calcification/ stiffness in the targeted eye tissues, and as a consequence, controls the development and progression of glaucoma. To develop and prove this hypothesis, we propose to investigate the response of Mgp to glaucomatous insults in vivo using the newly generated Mgp-Cre-reporter mice (SA#1), to override the early death of the Mgp KO by creating TM and ppSC specific conditional Knock-outs (cKOs) (SA#2) and to evaluate the impact of the specific ablations on glaucoma phenotypes (SA#3 Results to be obtained with the execution of this proposal will provide the mechanistic understanding and the knowledge needed to develop a combined TM-ppSC therapy which could potentially lead to a totally new treatment of glaucoma.

Public Health Relevance

The glaucomas are a group of optic neuropathies caused by the degeneration and death of the retinal ganglion cells. In glaucoma, there is a progressive visual field loss that if left untreated, leads to irreversible blindness. Primer Open Angle Glaucoma is the most common form of the disease, and is triggered in most cases by an elevated intraocular pressure (IOP). In turn, elevated IOP is the result of an increased resistance of the trabecular meshwork (TM) tissue to the outflow of the aqueous humor. In our laboratory we are interested in identifying genes and mechanisms involved in the development of glaucoma. Among the several candidates, one gene, Matrix Gla (MGP), could have important implications for both the understanding and the treatment of glaucoma. The gene is an inhibitor of calcification. It is responsible for pathological calcification in vascular diseases and in cancer. Its role in the eye is unknown. Interestingly, its expression is specifically localized to the TM and the peripapillary sclera (ppSC) surrounding the optic nerve head, two key tissues in the development of the disease. In this project, we propose to study the role of the Mgp gene in the eye of the living animal, by using transgenic technology. Findings from this project could lead to a new alternative treatment of glaucoma by targeting a common mechanism affecting both, the aqueous outflow at the trabecular meshwork and the biomechanical scleral strain at the ONH.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Diseases and Pathophysiology of the Visual System Study Section (DPVS)
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Liberman, Ellen S
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Borrás, Teresa (2018) Growth Factors, Oxidative Damage, and Inflammation in Exfoliation Syndrome. J Glaucoma 27 Suppl 1:S54-S60
Asokan, Priyadarsini; Mitra, Rajendra N; Periasamy, Ramesh et al. (2018) A Naturally Fluorescent Mgp Transgenic Mouse for Angiogenesis and Glaucoma Longitudinal Studies. Invest Ophthalmol Vis Sci 59:746-756
Keller, Kate E; Bhattacharya, Sanjoy K; Borrás, Theresa et al. (2018) Consensus recommendations for trabecular meshwork cell isolation, characterization and culture. Exp Eye Res 171:164-173
Borrás, Teresa (2017) A single gene connects stiffness in glaucoma and the vascular system. Exp Eye Res 158:13-22
Marulanda, Juliana; Eimar, Hazem; McKee, Marc D et al. (2017) Matrix Gla protein deficiency impairs nasal septum growth, causing midface hypoplasia. J Biol Chem 292:11400-11412
Borrás, Teresa (2017) The Pathway From Genes to Gene Therapy in Glaucoma: A Review of Possibilities for Using Genes as Glaucoma Drugs. Asia Pac J Ophthalmol (Phila) 6:80-93