# CHARACTERIZATION OF PURIFIED MYOCILIN: INSIGHT INTO GLAUCOMA

> **NIH NIH R01** · GEORGIA INSTITUTE OF TECHNOLOGY · 2022 · $76,702

## Abstract

Glaucoma, a leading cause of blindness worldwide (70 million patients), is managed medically by treating
the symptom of increased intraocular pressure (IOP), but 10% of patients still go blind. IOP is controlled in the
anterior segment of the eye, which contains the trabecular meshwork (TM) extracellular matrix, the anatomical
pathway for drainage of aqueous humor fluid. The TM tissue is diseased in most forms of glaucoma; loss of
TM homeostasis leads to elevated IOP. Hereditary open angle glaucoma, affecting ~3 million young patients,
is caused by mutations in myocilin, a protein highly expressed in the TM. Since 3/2011, studies funded from
R01EY021205 have changed the paradigm for anti-glaucoma therapeutics by laying the molecular foundation
for approaches that target the disease process, which are now being pursued in academia and industry.
 Studies from R01EY021205 have clarified molecular details of the toxic gain-of-function pathogenic
mechanism in which mutant myocilin accumulates in the endoplasmic reticulum (ER) of TM cells, leading to
TM cell death and an accelerated timeline for vision loss. Studies from R01EY021205 (a) contributed
fundamental knowledge of myocilin structure, (b) discovered a counter-productive interaction between myocilin
and the ER-resident Hsp90 chaperone Grp94, and (c) characterized myocilin misfolding as amyloid. Wild-type
and many different myocilin variants harbor a misfolding propensity; thus, proteostasis issues identified in
familial myocilin-associated glaucoma are likely at play in many more patients.
 Amyloid formation by myocilin places glaucoma alongside more well-studied amyloid diseases like
Alzheimer and SOD-1 dependent amyotrophic lateral sclerosis, yet comprehension of the role of amyloid in
glaucoma is in its infancy. The current objective is to better understand molecular aspects of myocilin
fibrilization, focused on the relevant olfactomedin (OLF) domain. The multidisciplinary team led by Raquel
Lieberman will (a) clarify initiation of aggregation by studying solution structures of wild-type and selected OLF
variants, as well as corresponding multi-length scale dynamics, using hydrogen-deuterium exchange mass
spectrometry and nuclear magnetic resonance (NMR) structure and relaxation methods (Wade Van Horn, Co-
I) (b) compare the end-point structures of selected OLF aggregates to known amyloids by solid state NMR
(Anant Paravastu, Co-I) and evaluate cytotoxicity of intermediate aggregates and (c) evaluate common allele
full-length myocilin variants for experimental hallmarks of pathogenicity. The expected outcome is a better
understanding of the myocilin misfolding process at the molecular level, including molecular determinants of
pathogenicity, to enable novel modalities for studying, diagnosing, and treating myocilin-associated glaucoma.
More broadly, continued structure/dysfunction studies of myocilin will not only contribute to an understanding of
glaucoma and its role in the TM, but will als...

## Key facts

- **NIH application ID:** 10622963
- **Project number:** 3R01EY021205-11S1
- **Recipient organization:** GEORGIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Raquel L Lieberman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $76,702
- **Award type:** 3
- **Project period:** 2011-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10622963

## Citation

> US National Institutes of Health, RePORTER application 10622963, CHARACTERIZATION OF PURIFIED MYOCILIN: INSIGHT INTO GLAUCOMA (3R01EY021205-11S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10622963. Licensed CC0.

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