# Lysosomal Enzymes in Outflow Pathway Physiology and Pathophysiology

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $447,684

## Abstract

SUMMARY
Defective aqueous humor (AH) drainage through the trabecular meshwork (TM) / Schlemm's cannal (SC)
conventional outflow pathway is usually associated to elevated intraocular pressure (IOP), and hence,
increased risk for developing glaucoma, a blinding disease second leading cause of permanent blindness in
the US. The nature of such resistance to AH outflow is far from being elucidated.
The TM consists of sheets of connective tissue beams lined by TM endothelial cells. Each beam is composed
of a central elastic core surrounded by collagen fibers embedded in a ground substance. The glaucomatous
outflow pathway is characterized by thickening of the trabecular lamellae and accumulation of long-spacing
collagen bundles and elastic fiber sheaths, which is presumed to stiffen the TM and prevent the tissue to
respond to mechanical cues. The exact causes underlying the deposit of extracellular material (ECM) and
thickening of the beams remain unknown; but it is likely a consequence of excessive synthesis of ECM
components, decreased proteolytic degradation, or both. Matrix metalloproteinases (MMPs) have been
historically believed to be the major proteases involved in ECM degradation; however, emerging evidence
indicates that while MMPs play a critical role in initiating ECM degradation in the extracellular environment,
other proteases or the coordinated action of several types of proteases (i.e. cysteine and serine proteases) are
responsible for the bulk matrix degradation, occurring pericellularly and intracellularly in the lysosomal
compartment, associated to lysosomal cathepsins. In agreement, studies conducted in our laboratory have
clearly demonstrated the constitutive cell surface expression and secretion of cathepsin B (CTSB) in TM cells
and its participation in the endocytic uptake and intralysosomal degradation of native and denature collagens.
Here we propose to investigate for the first time the contribution of a CTSB-mediated pericellular and
intracellular ECM degradative pathway in TM cells and the effect on outflow physiology. We hypothesize that
CTSB plays a critical role in ECM remodeling and outflow physiology by initiating a proteolytic
cascade leading to the pericellular and intracellular degradation of ECM components in TM cells. We
further hypothesize that modulation of CTSB activity may represent a novel therapeutic strategy in
glaucoma. To test this hypothesis, we will (1) demonstrate that CTSB associates with caveolae and initiates a
proteolytic cascade resulting in the partial degradation of ECM components; (2) determine the cell surface
receptors participating in of ECM components in TM cells; and (3) evaluate the effects of modulating CTSB
activity in outflow pathway function of murine glaucoma models.

## Key facts

- **NIH application ID:** 9931228
- **Project number:** 5R01EY027733-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Paloma Liton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $447,684
- **Award type:** 5
- **Project period:** 2017-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931228

## Citation

> US National Institutes of Health, RePORTER application 9931228, Lysosomal Enzymes in Outflow Pathway Physiology and Pathophysiology (5R01EY027733-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9931228. Licensed CC0.

---

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