# Retinal Iron Transport in Health and Disease

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $540,597

## 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 as follows: 1) Iron causes rapid retinal degeneration
following entry into the eye carried by an intraocular foreign body. 2) Human AMD retinas have
more iron than age-matched controls, suggesting that iron overload may play a role in AMD
pathogenesis. 3) Consistent with this hypothesis, in the inherited disease aceruloplasminemia,
loss of the ferroxidase ceruloplasmin (Cp) results in retinal iron accumulation and early onset
macular degeneration. 4) Mice with knockout for Cp and its homolog hephaestin (Heph) have an
age-dependent retinal iron overload and degeneration sharing features of AMD, including
complement activation and subretinal neovascularization. The latter two points indicate that Cp
and Heph are important for retinal health. Evidence from other organs suggests that Cp or Heph
can cooperate with the plasma membrane iron transporter ferroportin (Fpn) to export iron from
cells. Progress from the prior funding period indicates that Fpn is expressed on the ablumenal
side of retinal vascular endothelial cells, Muller cells, and the basolateral membrane of the RPE.
Since Fpn is the only known cellular iron exporter, this expression pattern suggests the route of
iron flux. Mice with a mutated Fpn that is resistant to degradation triggered by the iron regulatory
hormone Hepc, have retinal iron accumulation. These results suggest a local iron-regulatory
axis within the retina mediated by Fpn and Hepc. Experiments proposed herein will utilize retinal
cell type specific knockouts of Fpn and Hepc to determine the route of Fpn-mediated retinal iron
flux and evaluate its regulation by Hepc. AMD and control retinas will be analyzed to determine
whether Hepc/Fpn dysregulation contributes to the documented iron accumulation in AMD
retinas. The role of serum iron levels versus local control of iron influx into the retina will be
determined. The outcome will help focus AMD-iron clinical studies on either serum iron levels or
local iron regulatory mechanisms within the retina.

## Key facts

- **NIH application ID:** 10327706
- **Project number:** 5R01EY015240-17
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** JOSHUA L DUNAIEF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $540,597
- **Award type:** 5
- **Project period:** 2004-08-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10327706

## Citation

> US National Institutes of Health, RePORTER application 10327706, Retinal Iron Transport in Health and Disease (5R01EY015240-17). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10327706. Licensed CC0.

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