# Shedding Light on Glaucoma: Next Generation of Optogenetics for Aqueous Outflow Regulation

> **NIH VA I01** · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · 2024 · —

## Abstract

ABSTRACT
Glaucoma, a leading cause of irreversible blindness in the world, affects more than 285,000 U.S. veterans.
Elevated intraocular pressure (IOP) is associated with both development and progression of primary open
angle glaucoma, and IOP is the only modifiable risk factor for the disease. However, the mechanisms causing
elevated IOP remain poorly understood. Trabecular meshwork cells are critical to maintaining a normal
aqueous fluid flow and IOP. In other tissues, such as the kidney, bones and cartilage, the primary cilia play a
mechanosensory role in fluid flow. Here, we will explore the potential of cilia in trabecular meshwork cells to
serve a mechanosensory role in the eye. In our previous funding cycle, we demonstrated that phosphoinositide
lipids within primary cilia are an important regulator of eye pressure. We showed that phosphoinositide lipids
within primary cilia are tightly controled and that dysregulation produces elevated eye pressure. Using
optogenetic techniques, we targeted delivery of inositol enzymes to subcompartments within trabecular
meshwork cells to demonstrate their function in regulating IOP. Mutations in OCRL, an inositol polyphosphate
5-phosphatase, cause congenital glaucoma. We further identified a novel link between signaling by cilia
phosphoinositides and autophagy and lysosomal function. Here, we build on our strong preliminary evidence of
the power of optogenetic tools to develop a new optogenetic regulator for eye pressure based on OptoXRchimeric
G-protein coupled-receptor (GRCR) that has been shown to stimulate outflow facility. We hypothesize
that optogenetically regulated GRCR and phosphoinositide signaling within trabecular meshwork cells will
stimulate aqueous outflow. In Aim 1, we will determine whether reduction of IOP by GPR18 agonist PSBKD107
depends on primary cilia signaling. In Aim 2, we will determine whether chimeric OptoXR-GPR18 will
improve outflow facility. In Aim 3, we will determine whether GPR18 levels are reduced in trabecular meshwork
of open angle glaucoma patients. The proposed research is expected to have a significant impact on the
understanding of mechanosensation of eye pressure in mammals, which will facilitate the discovery of new
therapies for open angle glaucoma and other forms of glaucoma. Ultimately, the knowledge obtained from this
project will lead to novel therapeutic compounds for the many veterans suffering from vision loss.

## Key facts

- **NIH application ID:** 10703836
- **Project number:** 2I01CX001481-07
- **Recipient organization:** VETERANS ADMIN PALO ALTO HEALTH CARE SYS
- **Principal Investigator:** Yang Sun
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2016-10-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10703836

## Citation

> US National Institutes of Health, RePORTER application 10703836, Shedding Light on Glaucoma: Next Generation of Optogenetics for Aqueous Outflow Regulation (2I01CX001481-07). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10703836. Licensed CC0.

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