Retinal iron transport in health and disease

健康和疾病中的视网膜铁转运

• 批准号: 8662780
• 负责人: JOSHUA L DUNAIEF
• 金额: $ 61.84万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662780
• 关键词: Address; Affect; Age; Age related macular degeneration; All-Trans-Retinol; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Carrier Proteins; Cell membrane; Cells; Ceruloplasmin; Chelating Agents; Cleaved cell; Complement Activation; D Cells; Disease; Disease Progression; Equilibrium; Eye; Foreign Bodies; Funding; Glaucoma; Goals; Health; Hemorrhage; Homeostasis; Homologous Gene; Human; Hypoxia; In Vitro; Inherited; Iron; Iron Overload; Iron Regulatory Protein 2; Iron-Regulatory Proteins; Knock-out; Knockout Mice; Knowledge; Light; Macular degeneration; Mediating; Metabolism; Modeling; Movement; Muller' s cell; Mus; Mutation; Neural Retina; Oral Administration; Organ; Oxidants; Oxidative Phosphorylation; Oxidative Stress; Pathogenesis; Patients; Photoreceptors; Play; Primary Cell Cultures; Protein C; Proteins; Regulation; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Role; Structure of retinal pigment epithelium; Testing; Therapeutic; Tissues; Toxic effect; Transferrin; Work; age related; cell type; disorder of macula of retina; early onset; human tissue; in vivo; iron metabolism; membrane biogenesis; metal transporting protein 1; mouse model; neovascularization; novel; oxidative damage; protein activation; public health relevance; sodium iodate; therapeutic target

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.

描述(由申请人提供)：铁在健康和患病的视网膜中都扮演着重要的角色。拟议研究的长期目标是了解视网膜铁通量的调节，确定为什么铁在视网膜疾病中积聚，并发现如何预防视网膜铁中毒。铁是视网膜氧化磷酸化、膜生物发生和视黄醇异构化所必需的，但当调控不当时，铁会成为氧化应激的中心生产者。在视网膜疾病中，铁的毒性明显如下：1)在眼内异物进入眼睛后，铁会导致视网膜迅速退化。2)人类AMD视网膜中铁含量高于年龄匹配的对照组，提示铁超载可能在AMD的发病机制中起一定作用。3)与此假设一致的是，在遗传性疾病无纤维蛋白血症中，铜蓝蛋白铁氧合酶(CP)的缺失会导致视网膜铁蓄积和早发性黄斑变性。4)CP及其同系物Heph基因敲除小鼠的视网膜铁超载和退行性改变具有AMD的共同特征，包括补体激活和视网膜下新生血管。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间取得的进展表明，Heph在RPE铁输出中发挥着细胞自主的作用，但它在视网膜内铁运输中也具有关键功能。目前这项研究的目标之一是发现米勒细胞在视网膜铁调节中的作用。另一个目标是检验最近发现的第三种铁氧合酶--淀粉样前体蛋白(APP)--介导铁进入视网膜的假设。视网膜铁的进出口平衡由铁调节蛋白(Irps)控制。在疾病中，由于缺氧或氧化应激，这些蛋白可能会被失调。我们将评估IRPS在健康和患病视网膜的视网膜铁调节中的作用。利用原代细胞培养、系统和细胞类型特异性条件性基因敲除和死后人体组织进行的协同研究将增加我们对铁氧化酶和IRPS在健康和疾病中对视网膜铁的影响的理解。