# Matricellular Proteins in the Trabecular Meshwork Regulate Intraocular Pressure

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $396,250

## Abstract

Project Summary/Abstract
 Glaucoma is a leading cause of preventable blindness. Elevated intraocular pressure (IOP) is a
causitive risk factor and is due to altered drainage through the trabecular meshwork (TM). Extracellular matrix
(ECM) turnover is known to be one of the factors that influences IOP regulation in the TM, but little is known of
how ECM turnover is controlled. Furthermore, abnormal accumulations of ECM in the TM are seen in both
untreated and treated eyes with primary open-angle glaucoma (POAG) and is, thus, a primary disease
mechanism. Transforming growth factor beta-2 (TGF2) is elevated up to 3-fold in the aqueous humor of
POAG patients, and in various experimental systems, increases IOP with resultant alterations of ECM in the
TM. Matricellular proteins are non-structural secreted glycoproteins that facilitate cellular control over their
surrounding ECM. Matricellular proteins, and in particular SPARC, are associated with diseases of aberrent
fibrosis. Under the auspices of the prior grant, we demonstrated that SPARC regulates IOP and increases
fibronectin, collagens –I and –IV in the juxtacanalicular TM concurrent with decreased matrix
metalloproteinase-9 (MMP-9) activity. The molecular mechanisms causing the changes in ECM and MMP
activity are unclear. Integrin-linked kinase has been shown in other tissues as a downstream receptor for
SPARC and is known to affect MMP activity and the actin cytoskeleton. Furthermore, we and others have
shown that SPARC is the most highly expressed protein by TM cells in response to TGF2. We demonstrated
that TGFb2 regulates SPARC via smad3, JNK, and p38 signaling pathways. In SPARC -/- mice, there is a near
complete block of the IOP elevation normally seen with increased TGF2 indicating that SPARC is a critical
regulatory node in the pathophysiology of POAG.
 We hypothesize that suppressing SPARC or inhibiting SPARCs downstream effector, ILK, will
lower IOP in normotensive and TGF2-induced hypertensive models. As a chaperone, SPARC allows
accumulation of structural ECM proteins, especially COL4 and COL1, and the chaperone effect is
dependent on the pattern of glycosylation, a cell/tissue specific post-translational modification that could
potentially rectify incongruous observations of SPARC’s activity in different cell/tissue types. In this proposal,
we will determine the general chaperone capability of SPARC using established assays and ascertain the
effect of different glycosylation using surface plasmon resonance imaging on collagen binding. We will
suppress SPARC using shRNA and the metabolic breakdown product of SPARC by MMP-3, SZ-1, in perfused
anterior segment tissue, live mice, and TM cell cultures. We will determine the effect of inhibiting ILK, using
shRNA and a small molecule inhibitor of ILK, and inhibiting ILK after SPARC overexpression on the actin
cytoskeleton in TM cells as well as IOP and JCT ECM in both perfused anterior segment tissue and TM cells.

## Key facts

- **NIH application ID:** 9861245
- **Project number:** 5R01EY019654-09
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Douglas J Rhee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $396,250
- **Award type:** 5
- **Project period:** 2009-09-30 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9861245

## Citation

> US National Institutes of Health, RePORTER application 9861245, Matricellular Proteins in the Trabecular Meshwork Regulate Intraocular Pressure (5R01EY019654-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9861245. Licensed CC0.

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