# Molecular Mechanisms of Outflow Segmentation and Intraocular Pressure Homeostasis

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $336,105

## Abstract

Project Summary
Glaucoma is a major blinding disease. The primary risk factor and only current treatment target for all types of
glaucoma is elevated intraocular pressure (IOP). We have identified a robust IOP homeostatic mechanism in
which sustained pressure deviations are sensed as mechanical stretching/distortion by cells within the
juxtacanalicular (JCT) region of the outflow pathway and corrective adjustments are made to the outflow
resistance which restore IOP to appropriate levels. This appears to be a key reason that most people do not
develop glaucoma. We recently showed that glaucomatous anterior segments cannot execute a normal IOP
homeostatic response. Outflow is segmental around the circumference of the eye with regions of high flow (HF)
intermediate flow (IF) and low flow (LF). We recently showed that glaucomatous eyes have more LF regions
than normal eyes. This proposal is directed at understanding these two phenomena, IOP homeostasis and
outflow segmentation, and exploiting this understanding to correct the glaucomatous deficiencies in them.
 To begin understanding the IOP homeostatic process and outflow segmentation, we evaluated molecular
distribution differences between HF and LF regions of human anterior segments that had been perfused at 1x
(normal) or 2x (homeostatic response) pressures. We selected a subset of the molecular differences that seemed
most relevant to these processes; they were mostly extracellular matrix (ECM) proteins that function in ECM
organization and remodeling. We will refine their distributions, evaluate their regional biosynthesis/dynamics
rates, use RNAi silencing to knockdown their levels, interfere directly with their binding interactions, and conduct
a few select protein overexpression studies. Primary readouts will be outflow segmentation changes and outflow
facility changes in perfused human anterior segment organ culture. Next we will obtain the same molecular
distribution data for glaucomatous eyes and using the most effective RNAi silencing and binding interaction
perturbations from normal and apply them to glaucomatous eyes. The point will be to modify outflow
segmentation and IOP homeostatic responsiveness in diseased tissue to restore function.

## Key facts

- **NIH application ID:** 10478291
- **Project number:** 5R01EY025721-08
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** TED S ACOTT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $336,105
- **Award type:** 5
- **Project period:** 2015-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10478291

## Citation

> US National Institutes of Health, RePORTER application 10478291, Molecular Mechanisms of Outflow Segmentation and Intraocular Pressure Homeostasis (5R01EY025721-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10478291. Licensed CC0.

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