# Autophagy and Mechanotransduction in the Trabecular Meshwork

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $438,522

## Abstract

ABSTRACT
Functional failure of the trabecular meshwork (TM) conventional outflow pathway causes elevation in
intraocular pressure (IOP), thus increasing the risk for developing primary open angle glaucoma (POAG) an
age-related disease second leading cause of irreversible blindness. The homeostatic mechanisms responsible
for IOP regulation and those associated with its alteration in glaucoma remain yet poorly understood.
Because of elevation in IOP and other forces, cells in the trabecular meshwork (TM) are constantly subjected
to mechanical strain. In order to preserve cellular function and regain homeostasis, cells must sense and adapt
to these morphological changes. We and others have already shown that mechanical stress can trigger a
broad range of responses in TM cells; however, very little is known about the strategies that TM cells use to
respond to this stress, so they can adapt and survive.
Autophagy, a lysosomal degradation pathway, has emerged as an important cellular homeostatic mechanism
promoting cell survival and adaptation to a number of cytotoxic stresses. Our laboratory has reported the
activation of autophagy in TM cells in response to static biaxial strain and high pressure. Moreover, our newest
data also suggest the activation of chaperon-assisted selective autophagy, a recently identified tension-
induced autophagy essential for mechanotransduction, in TM cells under cyclic mechanical stress.
We hypothesize that autophagy is part of an integrated response triggered in TM cells in response to strain,
exerting a dual role in repair and mechanotransduction. We further hypothesize that dysregulation of this
response contributes to the increased ECM deposition and stiffness reported in the glaucomatous outflow
pathway. We propose that activation of autophagy can, therefore, represent a novel therapeutic approach for
the treatment of ocular hypertension and glaucoma. To test this hypothesis, we will (1) characterize the
induction of autophagy in TM cells in response to mechanical stress and high pressure and determine its
contribution to the stretch-induced response in TM cells; (2) assess a role of autophagy in modulating the
TGFβ-mediated pro-fibrotic response to mechanical injury, and (3) evaluate the ability of pharmacological
activators of autophagy to decrease ECM deposition and restore outflow pathway function. We anticipate that
completion of this project will definitively contribute to a further understanding of the role of autophagy in
outflow pathway tissue physiology and pathophysiology. Most importantly, our studies have the potential of
identifying a novel therapeutic target for the treatment of ocular hypertension and glaucoma.

## Key facts

- **NIH application ID:** 9979962
- **Project number:** 5R01EY026885-05
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Paloma Liton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $438,522
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979962

## Citation

> US National Institutes of Health, RePORTER application 9979962, Autophagy and Mechanotransduction in the Trabecular Meshwork (5R01EY026885-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9979962. Licensed CC0.

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