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.
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 conditions. 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.
|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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