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 our prior funding period indicates that Heph plays a cell-autonomous role in RPE iron export, but that it also has a critical function in inner retinal iron transport. One goal of the current proposal is t discover the role of Muller cell Heph in retinal iron regulation. Another goal is to test the hypothesis that a third, recently identified ferroxidase, amyloid precursor protein (APP), mediates iron import into the retina. The balance of retinal iron importers and exporters is controlled by iron regulatory proteins (IRPs). These can be dysregulated in disease by hypoxia or oxidative stress. We will assess the role of IRPs in retinal iron regulation in healthy and diseased retinas. The synergistic proposed studies using primary cell culture, systemic and cell-type specific conditional knockouts and post mortem human tissues will increase our understanding of the effects of ferroxidases and IRPs on retinal iron in health and disease.

Public Health Relevance

The proposed work on the mechanisms of retinal iron regulation is important for protecting human health because iron dysregulation can occur with age-related macular degeneration (AMD), glaucoma, retinitis pigmentosa, and intraocular hemorrhage or foreign body, most likely exacerbating these diseases. Our knowledge of retinal iron regulation in the normal retina and understanding of the mechanism of iron accumulation in retinal disease are incomplete. The proposed studies will increase understanding of these mechanisms and provide new mouse models for testing potential therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
4R01EY015240-12
Application #
9056530
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Neuhold, Lisa
Project Start
2003-11-01
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
12
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Fuqua, Brie K; Lu, Yan; Frazer, David M et al. (2018) Severe Iron Metabolism Defects in Mice With Double Knockout of the Multicopper Ferroxidases Hephaestin and Ceruloplasmin. Cell Mol Gastroenterol Hepatol 6:405-427
Saadane, Aicha; Petrov, Alexey; Mast, Natalia et al. (2018) Mechanisms that minimize retinal impact of apolipoprotein E absence. J Lipid Res 59:2368-2382
Hussnain, S Amal; Dolz-Marco, Rosa; Dunaief, Joshua L et al. (2018) SPECKLED HYPOAUTOFLUORESCENCE AS A SIGN OF RESOLVED SUBRETINAL HEMORRHAGE IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. Retina :
Sterling, Jacob; Guttha, Samyuktha; Song, Ying et al. (2017) Iron importers Zip8 and Zip14 are expressed in retina and regulated by retinal iron levels. Exp Eye Res 155:15-23
Baumann, Bailey; Sterling, Jacob; Song, Ying et al. (2017) Conditional Müller Cell Ablation Leads to Retinal Iron Accumulation. Invest Ophthalmol Vis Sci 58:4223-4234
Song, Delu; Sulewski Jr, Michael E; Wang, Chenguang et al. (2017) Complement C5a receptor knockout has diminished light-induced microglia/macrophage retinal migration. Mol Vis 23:210-218
Song, Delu; Wilson, Brooks; Zhao, Liangliang et al. (2016) Retinal Pre-Conditioning by CD59a Knockout Protects against Light-Induced Photoreceptor Degeneration. PLoS One 11:e0166348
Song, Delu; Song, Jiantao; Wang, Chenguang et al. (2016) Berberine protects against light-induced photoreceptor degeneration in the mouse retina. Exp Eye Res 145:1-9
Bhoiwala, Devang L; Dunaief, Joshua L (2016) Retinal abnormalities in ?-thalassemia major. Surv Ophthalmol 61:33-50
Theurl, Milan; Song, Delu; Clark, Esther et al. (2016) Mice with hepcidin-resistant ferroportin accumulate iron in the retina. FASEB J 30:813-23

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