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.
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.
|Guo, Lucie Y; Alekseev, Oleg; Li, Yafeng et al. (2014) Iron increases APP translation and amyloid-beta production in the retina. Exp Eye Res 129:31-7|
|Masuda, Tomohiro; Wahlin, Karl; Wan, Jun et al. (2014) Transcription factor SOX9 plays a key role in the regulation of visual cycle gene expression in the retinal pigment epithelium. J Biol Chem 289:12908-21|
|He, Lizhi; Marioutina, Mariya; Dunaief, Joshua L et al. (2014) Age- and gene-dosage-dependent cre-induced abnormalities in the retinal pigment epithelium. Am J Pathol 184:1660-7|
|Zhao, Liangliang; Wang, Chenguang; Song, Delu et al. (2014) Systemic administration of the antioxidant/iron chelator ?-lipoic acid protects against light-induced photoreceptor degeneration in the mouse retina. Invest Ophthalmol Vis Sci 55:5979-88|
|Fuqua, Brie K; Lu, Yan; Darshan, Deepak et al. (2014) The multicopper ferroxidase hephaestin enhances intestinal iron absorption in mice. PLoS One 9:e98792|
|Wolkow, Natalie; Li, Yafeng; Maminishkis, Arvydas et al. (2014) Iron upregulates melanogenesis in cultured retinal pigment epithelial cells. Exp Eye Res 128:92-101|
|Song, Delu; Grieco, Steve; Li, Yafeng et al. (2014) A murine RP1 missense mutation causes protein mislocalization and slowly progressive photoreceptor degeneration. Am J Pathol 184:2721-9|
|Song, Delu; Zhao, Liangliang; Li, Yafeng et al. (2014) The oral iron chelator deferiprone protects against systemic iron overload-induced retinal degeneration in hepcidin knockout mice. Invest Ophthalmol Vis Sci 55:4525-32|
|Zhao, Chen; Yasumura, Douglas; Li, Xiyan et al. (2011) mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice. J Clin Invest 121:369-83|
|Iacovelli, Jared; Zhao, Chen; Wolkow, Natalie et al. (2011) Generation of Cre transgenic mice with postnatal RPE-specific ocular expression. Invest Ophthalmol Vis Sci 52:1378-83|
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