# Molecular Mechanisms of Exfoliation Glaucoma

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $556,972

## Abstract

.ABSTRACT – Hauser/Stamer R01 .
Pseudoexfoliation (PEX) glaucoma is a blinding form of glaucoma clinically characterized by insoluble protein
deposits in the anterior chamber of the eye, and it is the most common identifiable secondary form of OAG,
accounting for ~7 million cases worldwide. Genome wide association studies have identified genetic variants in
the lysyl oxidase-like-1 (LOXL1) locus that are strongly associated with risk of PEX. Unfortunately, the functional
mechanisms by which this locus contribute to PEX glaucoma are unknown. Our recent report characterized a
long non-coding RNA (denoted herein as PEXpress) within the LOXL1 locus. We found that genetic variants
alter the promoter strength of PEXpress, and are strongly associated with PEX glaucoma. We have extended
these observations in preliminary experiments, revealing that knock down of PEXpress changes the expression
of hundreds of downstream target genes, and analysis reveals modifications in pathways that lead to ocular
hypertension including extracellular matrix remodeling and mechanotransduction. Using unbiased mass
spectrometry and direct binding assays, we discovered that PEXpress specifically binds to the mRNA processing
protein, hnRNPL via a 14 base pair binding region in PEXpress, and that endogenous hnRNPL complexes with
endogenous PEXpress in cell culture. Based upon these observations, we hypothesize that alterations in the
PEXpress/hnRNPL complex result in the dysregulation of downstream target genes, leading to altered trabecular
meshwork (TM) and Schlemm’s canal (SC) cell biology, conventional outflow function and ultimately, increased
intraocular pressure. To test this hypothesis, we have constructed three specific aims. In the first aim, we will
determine the role of the PEXpress/hnRNPL complex on gene and protein regulation in human conventional
outflow cells. Aim 2 is designed to determine the functional effects of the PEXpress/hnRNPL complex on human
conventional outflow cells. Aim 3 will determine the effects of PEXpress on outflow facility using perfused human
anterior segments in organ culture. As outcomes of this research we expect to (i) identify gene and protein
targets plus signaling pathways regulated by PEXpress /hnRNPL complex in cell types responsible for the
regulation of outflow resistance, (ii) identify role of PEXpress/hnRNPL in TM and SC cell signaling, contractility
and barrier function, plus (iii) determine the role of PEXpress on conventional outflow function in an intact model
system.

## Key facts

- **NIH application ID:** 10220041
- **Project number:** 5R01EY030617-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** MICHAEL A HAUSER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $556,972
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220041

## Citation

> US National Institutes of Health, RePORTER application 10220041, Molecular Mechanisms of Exfoliation Glaucoma (5R01EY030617-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10220041. Licensed CC0.

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