# Role of Clusterin in Aqueous Humor Outflow Physiology

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $384,362

## Abstract

Project Summary:
 Strong correlations exist between excessive structural changes in the trabecular meshwork (TM)-
juxtacanalicular tissue (JCT) of the aqueous humor (AH) outflow pathway. Increased outflow resistance
leads to elevated intraocular pressure (IOP), which is a major risk factor for primary open angle
glaucoma (POAG). POAG is the second leading cause of blindness in the United States. Lowering IOP
significantly halts the progression of the disease. The molecular players and mechanisms leading to the
excessive extracellular matrix (ECM) build-up and elevated IOP are complex and little understood.
Preliminary data in support of this proposal identifies clusterin, a secretory chaperone protein, as an
important regulator of IOP. We have identified that clusterin and its downstream target cathepsin k
(CTSK) regulates of cell-cytoskeleton and cell-ECM interactions in the aqueous humor outflow pathway
tissues. Based on this compelling evidence, we propose the CENTRAL HYPOTHESIZE that clusterin
plays a critical role in the IOP homeostasis and disruption of clusterin function can
contribute to POAG. The proposed study will mechanistically understand the role of clusterin in
aqueous outflow drainage and in POAG and offer new therapeutic opportunities.
 The scientific premise for this hypothesis stems from our preliminary data, which shows that loss
of clusterin results in increased fibrogenic activity in the TM outflow pathway and constitutive
expression of clusterin resulting in lowering of IOP by decreasing cell-cytoskeleton and cell-ECM
interactions. Given the convincing evidence for a key role played by clusterin in the TM, this project will
carefully examine the function of clusterin with three different aims. Aim 1 will test the hypothesis
that the loss of clusterin in the trabecular outflow pathway results in elevated IOP due to
defective ECM degradation and clearance. Aim 2 will test the hypothesis that clusterin
requires CTSK production and activation to lower IOP. Aim 3 will test the hypothesis that
direct delivery of clusterin into the anterior chamber reverses pathological ocular
hypertension.
 The proposed research is innovative because we have identified two key proteins - clusterin and
its downstream target cathepsin K in the regulation of IOP via modulation of ECM turnover and
remodeling. Key insights into the unknown functions of clusterin and cathepsin K will help in
developing modifiable therapeutic targets in the future to lower IOP.
Relevance to public health:
 Better understanding of the molecular mechanisms regulating homeostasis of aqueous humor
outflow resistance will provide novel clinical strategies to reduce IOP elevation and prevent vision loss.

## Key facts

- **NIH application ID:** 10240478
- **Project number:** 5R01EY029320-03
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Padmanabhan Paranji Pattabiraman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,362
- **Award type:** 5
- **Project period:** 2019-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240478

## Citation

> US National Institutes of Health, RePORTER application 10240478, Role of Clusterin in Aqueous Humor Outflow Physiology (5R01EY029320-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10240478. Licensed CC0.

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