Iron is necessary in the retina for oxidative phosphorylation, membrane biogenesis and retinol isomerization, but can also produce oxidative stress if improperly regulated, leading to cell death. This can contribute to retinal disease as follows: 1) Iron toxicity causes rapid retinal degeneration following direct entry of iron 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) Inherited defects in the ferroxidase ceruloplasmin (Cp) result in retinal iron accumulation and early onset macular degeneration. 4) Mice with mutation in Cp and its homolog hephaestin (Heph) have an age-dependent retinal iron overload and degeneration with a number of features similar to AMD, including 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. The goal of this proposal is to increase understanding of the roles of Cp, Heph and Fpn in retinal iron homeostasis and their regulation by the secreted hormone hepcidin (Hepc). Hepc is produced in the retina (as well as the liver) and triggers internalization and degradation of Fpn. Hepc may serve as a message from retinal cells sensing iron excess (such as photoreceptors) to degrade Fpn and limit iron transfer from RPE and Muller cells. Our existing Cp/Heph double mutant and Hepc-/- mice indicate that these three proteins are critical for retinal iron homeostasis and health, but provide little information about the specific functions of the proteins within the retina. Conditional mouse knockout technology (lox/cre) affords the opportunity to determine how these proteins function within specific retinal cell types and how intercellular iron transfer is executed and regulated.
In Aim1, the photoreceptor-specific functions of Heph, a possible """"""""iron release valve"""""""" to prevent PR iron overload will be investigated using a Heph conditional knockout on a Cp-/- background.
In Aim 2, the iron transport function of Fpn will be investigated using RPE and photoreceptor-specific conditional knockout mice.
In Aim 3, the retinal function of Hepc will be investigated in knockout and conditional knockout mice. These studies are important because: 1) They will provide new information about the cell-type specific functions of Heph, Fpn and Hepc and the routes of intercellular iron transfer that control retinal iron homeostasis. 2) The conditional knockout mice are likely to provide models for several features of AMD, including subretinal neovascularization while avoiding the lifespan-limiting brain iron overload in our existing Cp/Heph double mutant mice.

Public Health Relevance

The proposed work on the mechanisms of retinal iron transport is relevant to retinal health since iron overload has been implicated in age-related macular degeneration (AMD) and other retinal diseases. The mouse models resulting from mutation of iron transporters are expected, based on our previous work, to have features of AMD, including subretinal neovascularization, photoreceptor and RPE death, lipofuscin accumulation, and activation of the complement cascade. These models will provide a platform for understanding the mechanisms of retinal iron regulation and testing potential therapeutics for retinal disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY015240-07
Application #
8076195
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
2003-11-01
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
7
Fiscal Year
2011
Total Cost
$374,220
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 :
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
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; 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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