# Targeting ER Stress Pathway Using Sodium 4-Phenylbutyrate for the Treatment of POAG

> **NIH NIH R01** · UNIVERSITY OF NORTH TEXAS HLTH SCI CTR · 2020 · $361,320

## Abstract

Abstract
Primary open angle glaucoma (POAG), a major cause of irreversible blindness, is often associated with
elevated intraocular pressure (IOP) due to increased aqueous humor outflow resistance at the trabecular
meshwork (TM). The pathological mechanisms leading to glaucomatous TM damage and IOP elevation are
poorly understood. We have previously linked protein misfolding and endoplasmic reticulum (ER) stress to
development of glaucomatous TM damage and IOP elevation. Importantly, we demonstrated that targeting
abnormal myocilin accumulation and ER stress via small chemical chaperone, sodium 4-phenylbutyrate (PBA)
rescues mouse model of myocilin glaucoma, which accounts for ~4% of general POAG. Our long-term goal is
to determine whether PBA can be used for the treatment of the general POAG cases. Increased accumulation
of extracellular matrix (ECM) due to reduced activity of matrix metalloproteinases (MMPs) that degrade
extracellular ECM is implicated in the pathophysiology of general POAG. We have recently demonstrated that
increased ECM accumulation induces chronic ER stress in the TM of POAG. Moreover, our preliminary studies
suggest that PBA reduces ECM accumulation via induction and activation of MMPs. It is our central premise
that increased ECM accumulation induces chronic ER stress, leading to TM dysfunction and IOP elevation in
POAG and PBA reduces ECM accumulation and ER stress via induction and activation of MMPs. To test this
hypothesis, we will utilize primary human TM cells and mouse models of glucocorticoid (GC) or TGFβ2-induced
ocular hypertension and human perfusion cultured POAG eyes. Both GC or TGFβ2 are known to be involved in
the pathophysiology of glaucomatous TM damage via increased outflow resistance and increased ECM
accumulation in the TM. Based on our preliminary data that GCs activate TGFβ2 signaling, we will examine
whether TGFβ2 signaling regulates GC-induced glaucoma (Aim1). Considering the major role of TGFβ2 in the
pathogenesis of POAG, we will next determine whether TGFβ2 induces chronic ER stress, leading to TM
dysfunction and IOP elevation via genetic knockdown of key mediators of chronic ER stress (Aim 2). In Aim 3,
we will determine whether PBA improves outflow facility and prevents TGFβ2-induced ocular hypertension in
mice and ex-vivo human perfusion cultured eyes. We will also determine whether PBA reduces elevated IOP
via its non-chaperonin activity on induction and activation of MMPs. The proposed studies will provide
pathological mechanisms of TM dysfunction and target these pathologies via PBA for the treatment of general
POAG. Importantly, these studies will provide an important foundation for planned clinical trials for PBA at the
University of Iowa.

## Key facts

- **NIH application ID:** 9961612
- **Project number:** 5R01EY028616-03
- **Recipient organization:** UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
- **Principal Investigator:** Gulab Zode
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $361,320
- **Award type:** 5
- **Project period:** 2018-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961612

## Citation

> US National Institutes of Health, RePORTER application 9961612, Targeting ER Stress Pathway Using Sodium 4-Phenylbutyrate for the Treatment of POAG (5R01EY028616-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9961612. Licensed CC0.

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