# Identification of a new role of membrane‐type 1 matrix metalloproteinases in corneal neovascularization

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2023 · $399,750

## Abstract

Project Summary/Abstract
 Corneal neovascularization (NV) can be caused by severe corneal injury or infection and is a leading cause
of blindness. Balance of pro-angiogenic factors and anti-angiogenic factors are important to maintain avascular
corneal tissue. Pro-angiogenic factors such as VEGFA and FGF2 are highly induced in inflamed corneas and
lead to activation of its receptor proteins such as VEGFR2 and FGFR2. Membrane-type 1 matrix
metalloproteinase (MMP-14) is involved in remodeling of extracellular matrix (ECM) through its proteolytic
activity. Recent studies have revealed that MMP-14 is a regulator of VEGFA/VEGFR2-mediated corneal NV via
unique and selective cleavage of VEGFR1 which is a decoy receptor for VEGFR2. FGF2-induced corneal NV is
delayed in MMP-14 knockout (KO) mice, indicating there is some correlation between FGF2 and MMP-14.
However, how MMP-14 interacts with FGF2 is still largely unknown. The goal of this application is to characterize
mechanism of MMP-14 on regulation of FGFR2 levels via ADAM-9 enzyme. We demonstrated that FGFR2 level
was low in MMP-14 KO corneal fibroblast cells. On the other hand, ADAM-9, which is substrate of MMP-14, was
higher in MMP-14 KO fibroblast than WT cells. We have also discovered that expression of MMP-8, MMP-9, and
ADAM-17, all of which are underlying FGF2/FGFR2-system, were highly induced in WT than MMP-14 KO cells
upon stimulation of FGF2. Thus, inhibition of MMP-14 can reduce FGF2/FGFR2-mediated corneal NV and
inflammation. Furthermore, our results show that FDA-approved small molecule drugs, clioquinol, chloroxine,
and folic acid, all of which contain a quinoline scaffold, inhibit MMP-14 enzyme activity. We propose three specific
aims: (1) Mechanism of two enzyme cascades, MMP-14 and ADAM-9, to regulate FGFR2 level and expression
of FGF2/FGFR2-mediated MMPs; (2) investigate the effect of MMP-14 in FGF2/FGFR2-mediated corneal
inflammation; (3) Characterize quinoline analogs as selective MMP-14 inhibitors. We will complete these aims
using innovative techniques from molecular biology and biophysics in vitro and in vivo.

## Key facts

- **NIH application ID:** 10585794
- **Project number:** 1R01EY033758-01A1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Kyuyeon Han
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $399,750
- **Award type:** 1
- **Project period:** 2023-01-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10585794

## Citation

> US National Institutes of Health, RePORTER application 10585794, Identification of a new role of membrane‐type 1 matrix metalloproteinases in corneal neovascularization (1R01EY033758-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10585794. Licensed CC0.

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