# Mechanotransduction in Aqueous Outflow Regulation and Open Angle Glaucoma

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $383,750

## Abstract

PROJECT SUMMARY
Glaucoma is a leading cause of irreversible blindness worldwide. While the etiology of the disease is complex,
it is typically associated with elevated intraocular pressure (IOP) due to increased resistance to aqueous
humor outflow through the trabecular meshwork (TM). The human TM is approximately 20 fold stiffer in
glaucoma, suggesting a prominent role of TM mechanobiology. Although current outflow pathway models
estimate that the juxtacanalicular region of the TM contributes to 90-95% of the outflow resistance, it is widely
accepted that outflow itself is not uniform around the circumference of the TM, but is highly segmental with
regions of relatively high flow (HF), and low flow (LF). Although this has been recognized previously, nearly all
studies over the past few decades have essentially ignored this fact. Whether there are inherent differences in
TM cells of HF and LF regions and between non-glaucomatous and glaucomatous individuals remains unclear.
Preliminary data in support of this proposal shows that, with glaucoma tissues, there are more LF regions, they
are stiffer, and are associated with elevated matrix crosslinking enzyme activity. Conversely, HF regions are
softer, fewer, and have lower levels of crosslinking activity. Based on these and other observations, we have
hypothesized that there are innate differences in cells between the segmental flow regions, and these
directly regulate extracellular matrix (ECM) turnover, crosslinking, and outflow. The precise mechanism
that underlies the relative shift to increased LF regions is unclear. In order to mechanistically understand the
regulatory link between matrix biomechanics, composition, and segmental outflow, we will use two general
experimental approaches, (A) using perfused human anterior segment organ culture, we will compare
biomechanical and biochemical properties of HF and LF regions, measure crosslinking, and, isolate cells from
these; and (B) use cell derived matrices to determine cell-matrix interactions. Specifically, in Aim 1, we will
isolate TM cells from different flow regions of glaucomatous and non-glaucomatous TM, characterize cell
surface receptor distribution, and investigate their mechanotransduction response to biophysical stimuli. We
will also obtain and characterize cell derived ECM, and determine the effect that these ECM have on cellular
behavior. In Aim 2, we will ascertain and quantify the nature of ECM crosslinks, document differences in
crosslinking enzyme activity, and determine if inhibiting crosslinks changes the biomechanics and composition
of segmental regions in both normal and glaucomatous eyes. We will also determine if substratum
biomechanics modulates crosslinking in segmental flow cells. Finally, in Aim 3, we will use a targeted
approach to identify regulators of the homeostatic response and manipulate outflow regions. Particularly we
will target the specific role that ECM binding integrin α7β1 has in mediating outflow, ECM r...

## Key facts

- **NIH application ID:** 9858357
- **Project number:** 5R01EY026048-03
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Vijaykrishna Raghunathan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,750
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858357

## Citation

> US National Institutes of Health, RePORTER application 9858357, Mechanotransduction in Aqueous Outflow Regulation and Open Angle Glaucoma (5R01EY026048-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9858357. Licensed CC0.

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