# Retinal Iron Health in Transport and Disease

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $584,800

## Abstract

PROJECT SUMMARY
Iron plays a critical role in both the healthy and diseased retina. The long term goals of the
proposed studies are to understand regulation of retinal iron flux, determine why iron
accumulates in retinal disease, and discover how to protect against retina iron toxicity. Iron is
necessary in the retina for oxidative phosphorylation, membrane biogenesis and retinol
isomerization, but becomes a central producer of oxidative stress when improperly regulated.
Iron toxicity is evident in retinal disease: it causes rapid retinal degeneration following entry into
the eye carried by an intraocular foreign body. Iron accumulation has also been noted in retinal
diseases including AMD, where it may exacerbate oxidative stress. Further, patients with the
inherited disease aceruloplasminemia, caused by mutation of the ferroxidase ceruloplasmin
(Cp), have retinal iron accumulation with RPE pigment abnormalities, and occasionally early
onset macular degeneration. Mice with knockout for Cp and its homolog hephaestin (Heph)
have age-dependent retinal iron overload and degeneration of photoreceptors and RPE.
Evidence from other organs suggests that Cp or Heph can cooperate with the sole plasma
membrane iron exporter, ferroportin (Fpn), to export iron from cells. Yet, results from the
previous funding period indicate that retina-specific knockout of Fpn has no impact on retinal
iron levels while retina-specific knockout of Heph leads to retinal iron accumulation. These data
point to the importance of ferroxidases Cp and Heph for keeping intraocular iron in its ferric
(Fe3+) state. We will test this hypothesis using AAV-Cp gene therapy in the absence of Fpn, as
well as an oxidation resistant form of the lipid DHA, which will be tested for retinal protection
against reactive oxygen species produced by Fe2+.

## Key facts

- **NIH application ID:** 10849902
- **Project number:** 5R01EY015240-19
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** JOSHUA L DUNAIEF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $584,800
- **Award type:** 5
- **Project period:** 2004-08-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10849902

## Citation

> US National Institutes of Health, RePORTER application 10849902, Retinal Iron Health in Transport and Disease (5R01EY015240-19). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10849902. Licensed CC0.

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