# Targeting calcification/ stiffness in glaucoma with Matrix Gla

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $336,444

## Abstract

PROJECT DESCRIPTION
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, TGFβ 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.

## Key facts

- **NIH application ID:** 9980410
- **Project number:** 5R01EY026220-05
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Hua Mei
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $336,444
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980410

## Citation

> US National Institutes of Health, RePORTER application 9980410, Targeting calcification/ stiffness in glaucoma with Matrix Gla (5R01EY026220-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9980410. Licensed CC0.

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