# Optic Nerve Head Mechanobiology in Glaucoma

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $447,840

## Abstract

ABSTRACT
Glaucoma is the second leading cause of blindness in the developed world. Alterations in optic nerve head
(ONH) biomechanics and pathologic remodeling of associated connective tissues in the lamina cribrosa (LC)
and scleral are thought to be important in glaucomatous retinal ganglion cell axonal damage and vision loss.
Elevated intraocular pressure (IOP) is the only modifiable risk factor for glaucoma, although vision loss can
occur at normal IOP. IOP is a stress that imparts strain to the ONH. The role that mechanical strain and the
underlying cellular mechanotransduction pathways play in pathologic connective tissue remodeling of the ONH
and sclera in glaucoma remain poorly understood, however. Our central hypothesis is that cellular-level strain,
modulated by laminar and scleral tissue stiffness, drives mechanotransduction responses that cause
pathologic alterations in the ONH and scleral connective tissue/extracellular matrix (ECM) and lead to axonal
death. Furthermore, we propose that these factors underlie the variability in glaucoma susceptibility and
progression at all IOP levels. The goals of this proposal are to 1) to identify the biomechanical factors that
contribute to glaucoma susceptibility, and 2) identify the biomechanical and molecular determinants of
mechanically-induced cellular responses and connective tissue remodeling in glaucoma. To achieve this goal,
we will use a unilateral, inducible animal model of glaucoma with identical IOP endpoints, and human donor
eyes. In Aim 1, we will identify biomechanical risk factors for glaucoma and determine remodeling-induced
alterations in morphology and mechanical responses of the LC and sclera using optical coherence tomography
and 3D reconstructions. We will also determine the effect of chronic elevated IOP on
mechanotransduction/ECM remodeling pathways in tissues and cells harvested from this model at a defined
IOP insult and correlate this activity with changes in scleral/ONH material properties and axon loss. In Aim 2,
we will determine whether the pathways identified in the animal model are similarly regulated clinical records-
verified normal and glaucomatous human donor eyes. In Aim 3, we will determine the mechanical environment
that stimulates tissue remodeling using eye specific, multi-scale 3D computational models of eyes. These
studies will lead to identification of both biomechanical factors and cellular mechanotransduction pathways that
contribute to scleral/ONH ECM remodeling and glaucoma pathogenesis, with the goal of identifying new
therapeutic targets.

## Key facts

- **NIH application ID:** 9895804
- **Project number:** 5R01EY027924-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** J CRAWFORD DOWNS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $447,840
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895804

## Citation

> US National Institutes of Health, RePORTER application 9895804, Optic Nerve Head Mechanobiology in Glaucoma (5R01EY027924-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9895804. Licensed CC0.

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