# Deciphering the role of osteopontin in the aging eye and age-related macular degeneration

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $459,739

## Abstract

Summary
Dry age-related macular degeneration (AMD) is the leading cause of vision loss in the Western World with a
complex etiology. The fundamental abnormalities occurring in retinal pigment epithelial (RPE) resulting in
their progressive dysfunction and subsequent atrophy in AMD, are still not known. However, candidate
pathogenic pathways linked to the development of disease have emerged from the convergence of a sundry
of epidemiological, genetic, morphological, and biochemical studies, including inflammation, lipid
dysregulation, apoptosis, and RPE barrier dysfunction among others. Currently there are no drugs available
to treat dry AMD.
In this proposal we concentrate on investigating the biology and function of osteopontin (OPN), a matricellular
glycoprotein known for its involvement in the pathogenesis of a variety of neurodegenerative and systemic
diseases, in which inflammation is key, in part through its role as a macrophage recruitment and retention
factor. However, OPN reportedly plays a two-sided role having both pro- and anti-inflammatory properties.
Furthermore, OPN has also been shown to regulate cellular homeostasis effecting cell differentiation,
metabolism, autophagy, phagocytosis, and apoptosis to name a few. This potential paradox in the role of
OPN may in part be due to the fact that (1) OPN function is cell and tissue specific, and (2) most studies
have not delineated the roles of the different OPN isoforms, which include intracellular versus secreted OPN
and splice variants OPNa, b, and c. With this in mind, we propose to systematically investigate the role of
OPN in AMD vulnerable cells with a focus on RPE biology and test the therapeutic potential of modifying
OPN levels in animal models that present with dry ‘AMD-like’ pathologies.
Published studies and key preliminary observations that precipitated pursuing this study include (1)
circulating soluble OPN (sOPN) levels increase in a subpopulation of individuals with age; (2) the role of
intracellular OPN, is less known but associated with amelioration of inflammation; (3) intracellular OPN
expression in human RPE cells is decreased in early dry AMD donor tissue; (4) secreted OPN accumulates
extracellularly in drusen and basal deposits of human AMD donor tissue; (5) plasma OPN is elevated in late
dry AMD patients; and (6) human RPE cells secrete OPN following oxidant injury and are a potential local
source. Based on our preliminary data and the known paradoxical anti- and pro-inflammatory roles of OPN
in neurodegenerative and systemic diseases that share common pathogenic pathways with AMD, we will
test the hypotheses that OPN regulates inflammation, aberrant RPE barrier function, and cell homeostatic
mechanisms, in an isoform dependent manner.

## Key facts

- **NIH application ID:** 10872169
- **Project number:** 5R01EY035126-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Goldis Malek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $459,739
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872169

## Citation

> US National Institutes of Health, RePORTER application 10872169, Deciphering the role of osteopontin in the aging eye and age-related macular degeneration (5R01EY035126-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10872169. Licensed CC0.

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