Retinal iron transport in health and disease

描述（由申请人提供）：铁在健康和患病的视网膜中都起着关键作用。拟议研究的长期目标是了解视网膜铁通量的调节，确定铁在视网膜疾病中积累的原因，并发现如何防止视网膜铁毒性。铁在视网膜中是氧化磷酸化、膜生物发生和视黄醇异构化所必需的，但当调节不当时，铁成为氧化应激的中心产生者。铁毒性在视网膜疾病中是明显的，如下：1）铁在由眼内异物携带进入眼睛后引起快速视网膜变性。2)人类AMD视网膜比年龄匹配的对照组具有更多的铁，这表明铁过载可能在AMD发病机制中起作用。3)与该假设一致，在遗传性疾病aceruloplasminemia中，铁氧化酶铜蓝蛋白（Cp）的损失导致视网膜铁积累和早发性黄斑变性。4)敲除Cp及其同源物赫啡肽（Heph）的小鼠具有年龄依赖性视网膜铁过载和退行性变，具有AMD的特征，包括补体激活和视网膜下新生血管形成。后两点表明Cp和Heph对视网膜健康很重要。来自其他器官的证据表明，Cp或Heph可以与质膜铁转运蛋白（Fpn）合作，从细胞中输出铁。从我们之前的资助期的进展表明，Heph在RPE铁输出中起着细胞自主作用，但它在视网膜内铁转运中也具有关键作用。本研究的目的之一是揭示Muller细胞Heph在视网膜铁调节中的作用。另一个目标是检验第三种最近鉴定的铁氧化酶，淀粉样前体蛋白（APP）介导铁进入视网膜的假设。视网膜铁输入者和输出者的平衡由铁调节蛋白（IRP）控制。这些可以在疾病中通过缺氧或氧化应激失调。我们将评估IRP在健康和患病视网膜的视网膜铁调节中的作用。使用原代细胞培养、系统性和细胞类型特异性条件性敲除以及死后人体组织的协同拟议研究将增加我们对铁氧化酶和IRP在健康和疾病中对视网膜铁的影响的理解。

DESCRIPTION (provided by applicant): 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.