# Control of Trabecular Meshwork Cytoskeleton

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $440,838

## Abstract

The long-term objective of this grant is to identify how to modulate αvβ3 integrin signaling
pathways in order to develop therapeutic targets to control intraocular pressure (IOP) in glaucoma. The
glaucomas, which lead to irreversible loss of retinal ganglion cells, affect approximately 67 million people
worldwide. They are commonly associated with elevated levels of intraocular pressure (IOP) due to a reduction
in aqueous humor outflow from the trabecular meshwork (TM). One of the major risk factors that has emerged
as an important regulatory mechanism for outflow facility is the actin cytoskeleton. It controls a number of key
biological processes involved in maintaining normal outflow facility including contractility, phagocytosis, and
deposition of the extracellular matrix. Integrins play a central role in regulating these cytoskeleton-mediated
activities and our studies suggest that dysregulation of the αvβ3 integrin causes the major phenotypic changes
associated with glaucoma including decreased phagocytosis, increased extracellular matrix deposition, CLAN
formation and an elevation in IOP. We propose that this integrin is activated in glaucoma by elevated levels of
TGFβ2 or following treatments with glucocorticoids, like dexamethasone (DEX).
 In this grant, we plan to use RNAseq studies to identify the factors upregulated by DEX or TGFβ2 that
activate αvβ3 integrin and proximity ligation assays to determine if these factors are associated with the
integrin adhesome. We also plan to demonstrate that an NRON/NFAT complex controls DEX-induced
activation of αvβ3 integrin and the secondary glucocorticoid response involved in steroid-induced glaucoma.
Finally, we plan to show that the responses to DEX (ECM formation, IOP elevation, and outflow facility) are
affected by the activated state of αvβ3 integrin in vivo, not just its expression level. To test this last hypothesis
we plan to use a tamoxifen inducible CreERcag-β3 integrinflox/flox mouse to knock down αvβ3 integrin
expression in the mouse TM. Adenoviral (Ad5) vectors expressing 3 different activated states of αvβ3 integrin
(wildtype, inactive and constitutively active) will be used to alter the activity levels of αvβ3 integrins in vivo.
 The proposed studies are the first to demonstrate that changes in a specific integrin signaling
pathway can affect IOP, outflow facility, and ECM formation in vivo. They will enhance our understanding
of how integrin signaling events are controlled in the TM and how this affects the cytoskeletal events (ECM
deposition, cell contractility and phagocytosis) that regulate outflow facility. Understanding how integrins
contribute to the regulation of these processes is important because it will enable us to provide new therapeutic
targets to regulate the cytoskeleton in order to restore homeostasis and decrease IOP.

## Key facts

- **NIH application ID:** 10316183
- **Project number:** 5R01EY017006-13
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Donna M Peters
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $440,838
- **Award type:** 5
- **Project period:** 2006-09-15 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10316183

## Citation

> US National Institutes of Health, RePORTER application 10316183, Control of Trabecular Meshwork Cytoskeleton (5R01EY017006-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10316183. Licensed CC0.

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