# Determining Molecular Mechanisms of Human Glaucoma Genes

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $411,526

## Abstract

ABSTRACT
Glaucoma, a major cause of blindness worldwide, is a significant public health concern. In the U.S., it affects
over 2.7 million people and its prevalence will rise to 7.3 million by 2050. Targeted therapies are needed to
prevent glaucoma or slow its progression. A major risk factor is high intraocular pressure (IOP), typically due to
impaired aqueous humor (AqH) outflow. However, the genes and pathways involved are poorly understood.
We have identified GLIS1, encoding the transcription factor GLIS1, as a susceptibility gene for primary open-
angle glaucoma (POAG) and showed that Glis1–/– mice have pathophysiological hallmarks of glaucoma. We
also found that Glis1 is predominantly expressed in the trabecular meshwork (TM), a key component of the
ocular drainage tissue regulating AqH outflow, and that Glis1–/– mice exhibit progressive TM degeneration,
leading to high IOP, and glaucomatous optic neuropathy—highlighting the relevance of this model for studies
of glaucoma. Our preliminary functional genomic analysis suggested that GLIS1 interacts with GLIS3 and
FOXC1, transcription factors previously implicated in elevated IOP, to regulate gene expression in TM cells.
Moreover, reduced or increased GLIS1 activity can impair the integrity of ocular drainage tissues. Using unique
mouse models, genetic and functional genomic approaches, and in vitro assays, we propose to characterize
the GLIS1-dependent transcriptional regulatory network and determine its role in homeostasis and dysfunction
of ocular drainage tissue. In Aim 1, we will test the hypothesis that increased GLIS1 expression contributes to
POAG-associated ocular drainage tissue defects and determine whether the POAG-associated variants we
identified in GLIS1 enhancer regions increased its transcriptional activity in primary human TM cells. We will
also test whether GLIS1 overexpression in the mouse TM leads to high IOP and ocular drainage tissue defects
similar to those in POAG. Finally, we will assess the potential role of dexamethasone and TGFβ2, previously
implicated in IOP elevation, as upstream regulators of GLIS1. In Aim 2, we will test for potential genetic
interactions between Glis1 and Foxc1 and/or Glis3 in ocular drainage tissue homeostasis. We will determine
whether mice heterozygous for null alleles of both Glis1 and Foxc1 or Glis1 and Glis3 develop TM defects and
altered IOP regulation. In parallel, we will characterize the transcriptional program and molecular pathways
implicated in TM maintenance and function. These studies will provide important mechanistic insight into ocular
drainage tissue homeostasis and dysfunction and could reveal targets for therapies to manage glaucoma.

## Key facts

- **NIH application ID:** 10444972
- **Project number:** 1R01EY033015-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Kayarat Saidas Nair
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $411,526
- **Award type:** 1
- **Project period:** 2022-05-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10444972

## Citation

> US National Institutes of Health, RePORTER application 10444972, Determining Molecular Mechanisms of Human Glaucoma Genes (1R01EY033015-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10444972. Licensed CC0.

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