# Molecular mechanisms of mechanotransduction in the aqueous outflow pathway

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $385,000

## Abstract

PROJECT SUMMARY/ABSTRACT
There is substantial evidence that hypertensive glaucoma dramatically alters the capacity of trabecular
meshwork (TM) cells to cope with mechanical stress, which in turn contributes to impaired drainage of aqueous
humor from the anterior eye. Functional loss is associated with stiffening of TM cells and their matrix, and with
loss of homeostatic mechanosensing that adjusts the resistance of the outflow pathway to the intensity of
experienced pressure and dynamics of aqueous humor flow. Fibrotic remodeling that underlies the increase in
flow resistance can be caused by chronic elevations in intraocular pressure (IOP) or by the cytokine TGF which
induces it in the absence of mechanical stress. There are currently no conceptual tools to link IOP stress, stages
of TM damage, TGF modulation and mechanotransduction in healthy and glaucomatous eyes into a unified
coherent mechanistic model.
The goal of this competing renewal is to test hypotheses about how TM cells navigate their response to pressure,
shear, and strain, how these mechanisms are reorganized in glaucoma and how matrix stiffness and TGF act
through mechanosensitive channels to serve as triggers for fibrotic remodeling that leads to functional loss in
glaucoma. Aim 1 will establish the roles of TRPV4 and Piezo1 channels in IOP regulation in conditional knockout
mouse models and ex vivo studies of conventional outflow. Aim 2 investigates the molecular foundation of
abnormal mechanotransduction in glaucomatous TM cells, studies the role of extracellular matrix as a central
determinant of mechanosensitivity, dissects the paradoxical dissonance between TRPV4 gene/protein
expression and function, and tests hypotheses about involvement of mechanochannels in intracellular stress
signaling, contractility, epithelial mesenchymal transition and regulation of cells’ proliferative potential. The goal
of Aim 3 is to bring together mechanotransduction and TGF signaling into a unified framework that would
accounts for biophysical (mechanical) and biochemical induction of many types of glaucoma. Upon completion
of the study we hope to expand our understanding of the complexity of interlocked molecular mechanisms
through which the TM regulates outflow facility, define the molecular triggers through which glaucoma hijacks
homeostatic force sensing by mechanosensitive ion channels, integrins and the cytoskeleton, and identify
strategies to mitigate injury by restoring the cells ability to autoregulate the mechanoresponse.

## Key facts

- **NIH application ID:** 10857184
- **Project number:** 5R01EY027920-07
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** DAVID KRIZAJ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2017-04-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10857184

## Citation

> US National Institutes of Health, RePORTER application 10857184, Molecular mechanisms of mechanotransduction in the aqueous outflow pathway (5R01EY027920-07). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10857184. Licensed CC0.

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