Retinal Iron Transport in Health and Disease

健康和疾病中的视网膜铁转运

• 批准号: 10327706
• 负责人: JOSHUA L DUNAIEF
• 金额: $ 54.06万
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327706
• 关键词: Aceruloplasminemia; Age; Age related macular degeneration; All-Trans-Retinol; Blood Circulation; Carrier Proteins; Cell membrane; Cells; Ceruloplasmin; Clinical Research; Complement; Complement Activation; Defect; Deposition; Disease; Enterocytes; Enzyme-Linked Immunosorbent Assay; Eye; Foreign Bodies; Funding; Genes; Glaucoma; Goals; Health; Hemorrhage; Hereditary Disease; Histologic; Homeostasis; Homologous Gene; Hormones; Human; Immunofluorescence Immunologic; Impairment; Intestines; Iron; Iron Chelating Agents; Iron Overload; Knock-out; Knockout Mice; Knowledge; Liver; Macular degeneration; Mediating; Metabolism; Molecular; Muller' s cell; Mus; Mutate; Mutation; Neural Retina; Oral Administration; Organ; Outcome; Oxidative Phosphorylation; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pattern; Photoreceptors; Play; Regulation; Resistance; Retina; Retinal Degeneration; Retinal Diseases; Retinal Pigments; Retinitis Pigmentosa; Role; Route; Sampling; Serum; Serum Iron Level; Side; Structure; Structure of retinal pigment epithelium; Testing; Therapeutic; Tissues; Toxic effect; Transferrin; Vascular Endothelial Cell; Vascular Endothelium; Work; age related; basolateral membrane; cell type; disorder of macula of retina; early onset; experimental study; hepcidin; iron metabolism; membrane biogenesis; metal transporting protein 1; mouse model; neovascularization; novel; null mutation; oxidative damage; peptide hormone; prevent; therapeutic target; uptake

PROJECT SUMMARY 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.

项目总结 铁在健康和患病的视网膜中都起着至关重要的作用。的长期目标 建议的研究是为了了解视网膜铁通量的调节，确定为什么铁 在视网膜疾病中积累，并发现如何防止视网膜铁中毒。铁是 视网膜中氧化磷酸化、膜生物发生和视黄醇的必需 异构化，但当调控不当时，它会成为氧化应激的中心生产者。 铁的毒性在视网膜疾病中很明显：1)铁导致视网膜快速退化 眼内异物进入眼内后进入眼睛。2)人类AMD视网膜有 与年龄匹配的对照组相比，铁含量更高，这表明铁超载可能在AMD中起作用 发病机制。3)与这一假设一致，在遗传性疾病无浆蛋白血症中， 铜蓝蛋白铁氧合酶(CP)的缺失会导致视网膜铁蓄积和早期发病 黄斑变性。4)CP及其同系物Heph基因敲除的小鼠有一个 AMD的年龄相关性视网膜铁超载和退行性改变的共同特征，包括 补体激活与视网膜下新生血管。后两点表明CP 和HEH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，将铁从 细胞。上一个供资期间的进展情况表明，FPN是在开腹小脑上表达的 视网膜血管内皮细胞、Muller细胞和RPE的基底膜。 由于FPN是唯一已知的细胞铁输出器，这种表达模式表明 铁熔剂。FPN突变的小鼠对铁调节引发的降解具有抵抗力 荷尔蒙HEPC，有视网膜铁蓄积。这些结果表明，当地的铁监管机构 FPN和HepC介导的视网膜内轴突。这里提出的实验将利用视网膜 细胞类型特异性敲除FPN和HEPC确定FPN介导的视网膜铁的途径 并评价HEPC对其调节作用。AMD和对照视网膜将被分析以确定 HEPC/FPN异常是否与AMD铁蓄积有关 视网膜。血清铁水平与局部控制进入视网膜的铁的作用将是 下定决心。这一结果将有助于将AMD-Iron的临床研究集中在血清铁水平或 视网膜内的局部铁调节机制。