# Retinal Disease Promoted by Iron-Induced Bisretinoid Oxidation

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $530,831

## Abstract

Retinal pigment epithelial (RPE) cells accumulate iron with age, and in diseases that threaten vision including
age-related macular degeneration (AMD), recessive Stargardt disease (STGD1) and aceruloplasminemia.
Unrestrained free iron can cause redox imbalance due to iron-catalyzed formation of highly reactive hydroxyl
free radical from hydrogen peroxide. The oxidative burden to which RPE is subjected also originates from a
mixture of retinaldehyde-adducts (bisretinoids) that accumulate with age as lipofuscin. The damaging effects of
these compounds on RPE cells are implicated in a number of age-associated and early-onset forms of retinal
disease including STGD1 and AMD. The adverse effects of these pigments are likely due, at least in part, to
their propensity to photogenerate reactive oxygen species and to photodegrade into damaging dicarbonyl and
aldehyde-bearing fragments. The broad objectives of the proposed studies are to understand whether iron can
interact with bisretinoids in the RPE to promote RPE cell damage and death. The central hypothesis of this
proposal is that dysregulated intracellular iron mediates adverse effects in part by promoting bisretinoid
oxidation and degradation. If redox imbalance is potentiated by a combination or iron and bisretinoid
photooxidation, iron chelation may be retina-protective in diseases involving bisretinoid toxicity including
STGD1. In Specific Aim 1, we will determine the effects of deferiprone (DFP)-treatment in Abca4-/- mice. DFP
is a clinically important iron chelator that serves to reduce iron levels. Using DFP we will test for protection
against iron-mediated bisretinoid oxidation and photoreceptor cell loss in Abca4-/- mice. Oxidative stress will
be assessed using a panel of redox indicators and cell-based and cell-free assays will be employed. In Specific
Aim 2, we propose to determine whether supplemental iron contributes to the photooxidation/oxidation and
degradation of bisretinoid. This aim will be achieved using mouse, cell and cell-free assays. We will ascertain
whether one of the pathways by which iron mediates toxicity is by promoting bisretinoid oxidation. We will also
establish whether intracellular iron is elevated in Abca4-/- mice, a model of STGD1. In experiments presented in
Specific Aim 3 we will study mice that are deficient in ceruloplasmin (Cp) and hephaestin (Heph), ferroxidase
proteins that convert ferrous (Fe2+) to ferric (Fe3+) iron so as to promote cellular iron export. Effects on the
phenotype of the Cp-/-;Heph-/- mouse will be assessed when an inhibitor of bisretinoid formation is
administered; in Abca4-/-; Cp-/-;Heph-/- mice which will have high levels of both iron and bisretinoids in the RPE,
and when no RPE bisretinoid (Rpe6rd12) and deficiency in Cp-/-;Heph-/- are combined in Rpe6rd12; Cp-/-;Heph-/-
mice. Completion of this research will advance our understanding of how, iron, light and bisretinoids combine
to contribute to disease processes in age-related and mon...

## Key facts

- **NIH application ID:** 9857612
- **Project number:** 5R01EY028131-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Janet Ruthe Sparrow
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $530,831
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857612

## Citation

> US National Institutes of Health, RePORTER application 9857612, Retinal Disease Promoted by Iron-Induced Bisretinoid Oxidation (5R01EY028131-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9857612. Licensed CC0.

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