# Investigation of ADAMTS in glaucoma pathogenesis

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $375,352

## Abstract

Project Summary/Abstract
 Primary open angle glaucoma (POAG) is an optic neuropathy with a characteristic pattern of visual field
loss and optic disc cupping due to progressive degeneration of retinal ganglion cells (RGCs). Elevated
intraocular pressure (IOP) is an important risk factor for POAG, and artificially raising IOP is very effective at
inducing glaucoma in animal models. However, the relationship between IOP and RGC death is unclear since
some patients with normal IOP develop glaucoma while others with elevated IOP do not. Our group made a
breakthrough discovery that a mutation in ADAMTS10 causes POAG in Beagle dogs. This finding was
independently validated and expanded by identification of another mutation in ADAMTS10 causing POAG in
Norwegian Elkhound dogs and 3 other mutations in a closely-related gene, ADAMTS17, in 3 other dog breeds.
Relevant to human glaucoma, an ADAMTS8 locus has been identified associated with vertical cup -disc ratio.
These findings suggest that mutations in ADAMTS genes cause POAG. In humans, null mutations of
ADAMTS10 cause Weill-Marchesani syndrome, a disease associated with defective microfibrils and
characterized by short skeletal features, lens dislocation and glaucoma. ADAMTS10 is a microfibril-associated
protein that plays a role in microfibril structure and function. Microfibrils are components of the extracellular
matrix that are key regulators of Transforming Growth Factor Beta (TGFβ) signaling and contribute to
mechanotransduction involving ligand-independent activation of the Angiotensin II Type I Receptor (AT1R).
Hyper-activation of TGFβ signaling and altered mechanotransduction are key pathogenic mechanisms for both
microfibril deficiencies and POAG. Identification of a microfibril-associated gene as causative for POAG led us
to formulate our central hypothesis that ADAMTS10 mutations cause glaucoma by disrupting microfibril
structure and function. Establishing microfibril defects as a disease mechanism would suggest that treatments
effective in other diseases caused by microfibril deficiencies may be applied to POAG. AT1R blockers (ARBs)
are effective in treating diseases associated with microfibril deficiencies and they have been considered as
potential glaucoma treatments owing to their IOP-lowering and neuroprotective effects. Based on our
microfibril hypothesis, we will test the efficacy of ARBs in treating glaucoma caused by ADAMTS10 mutations.
For this project, we will use mouse and zebrafish lines homozygous for glaucoma-causing mutations in
Adamts10. In Specific Aim 1, we will test the fundamental hypothesis that microfibril deficiencies cause POAG.
In Specific Aim 2, we will investigate molecular mechanisms of POAG caused by ADAMTS10 mutations. In
Specific Aim 3, we will test the efficacy of ARBs in treating or preventing glaucoma phenotypes caused by
ADAMTS10 mutations.

## Key facts

- **NIH application ID:** 10133667
- **Project number:** 5R01EY027746-05
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** JOHN G KUCHTEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $375,352
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133667

## Citation

> US National Institutes of Health, RePORTER application 10133667, Investigation of ADAMTS in glaucoma pathogenesis (5R01EY027746-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10133667. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*