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Retinal Disease Promoted by Iron-Induced Bisretinoid Oxidation

铁诱导的双维A酸氧化促进视网膜疾病

基本信息

批准号：
10090468
负责人：
Janet Ruthe Sparrow
金额：
$ 49.93万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10090468
关键词：
4 hydroxynonenal Abbreviations Aceruloplasminemia Address Adverse effects Affect Age Age related macular degeneration Aldehydes Biological Biological Assay Cell Death Cells Ceruloplasmin Cessation of life Chemicals Clinical Collaborations Complex Mixtures Coupled Data Deposition Disease Electron Transport Enzyme-Linked Immunosorbent Assay Eye FDA approved Family Free Radicals Fundus Glutathione Disulfide Glyoxal High Pressure Liquid Chromatography Hydrogen Peroxide Hydroxyl Radical Inductively Coupled Plasma Mass Spectrometry Influentials Investigation Iron Iron Chelating Agents Iron Chelation Legal Blindness Light Link Lipofuscin Liquid Chromatography Mediating Metabolism Modeling Mus Mutation Nuclear Optical Coherence Tomography Oral Oxidation-Reduction Oxidative Stress Oxides Pathogenicity Pathway interactions Patients Pennsylvania Performance Pharmacology Phenotype Phosphatidylethanolamine Photoreceptors Pigments Plasma Process Productivity Proteins Public Health Pyruvaldehyde Quantitative Reverse Transcriptase PCR Reactive Oxygen Species Regulation Research Research Personnel Retina Retinal Degeneration Retinal Diseases Retinaldehyde Retinitis Pigmentosa Retinol dehydrogenase Reverse Transcriptase Polymerase Chain Reaction Siderosis Solvents Source Sparrows Spectrometry, Mass, Electrospray Ionization Stargardt&apos s disease Structure Structure of retinal pigment epithelium Testing Therapeutic Thinness Time Toxic effect Universities Vision Work adduct age related base cell injury early onset experimental study ferric ammonium citrate fluorophore genetic approach imaging modality induced pluripotent stem cell inhibitor/antagonist iron supplement macromolecule oxidation visual cycle

项目摘要

Retinal pigment epithelial (RPE) cells accumulate iron with age, and in diseases that threaten vision including age-related macular degeneration (AMD), recessive Stargardt disease (STGD1) and aceruloplasminemia. Unrestrained free iron can cause redox imbalance due to iron-catalyzed formation of highly reactive hydroxyl free radical from hydrogen peroxide. The oxidative burden to which RPE is subjected also originates from a mixture of retinaldehyde-adducts (bisretinoids) that accumulate with age as lipofuscin. The damaging effects of these compounds on RPE cells are implicated in a number of age-associated and early-onset forms of retinal disease including STGD1 and AMD. The adverse effects of these pigments are likely due, at least in part, to their propensity to photogenerate reactive oxygen species and to photodegrade into damaging dicarbonyl and aldehyde-bearing fragments. The broad objectives of the proposed studies are to understand whether iron can interact with bisretinoids in the RPE to promote RPE cell damage and death. The central hypothesis of this proposal is that dysregulated intracellular iron mediates adverse effects in part by promoting bisretinoid oxidation and degradation. If redox imbalance is potentiated by a combination or iron and bisretinoid photooxidation, iron chelation may be retina-protective in diseases involving bisretinoid toxicity including STGD1. In Specific Aim 1, we will determine the effects of deferiprone (DFP)-treatment in Abca4-/- mice. DFP is a clinically important iron chelator that serves to reduce iron levels. Using DFP we will test for protection against iron-mediated bisretinoid oxidation and photoreceptor cell loss in Abca4-/- mice. Oxidative stress will be assessed using a panel of redox indicators and cell-based and cell-free assays will be employed. In Specific Aim 2, we propose to determine whether supplemental iron contributes to the photooxidation/oxidation and degradation of bisretinoid. This aim will be achieved using mouse, cell and cell-free assays. We will ascertain whether one of the pathways by which iron mediates toxicity is by promoting bisretinoid oxidation. We will also establish whether intracellular iron is elevated in Abca4-/- mice, a model of STGD1. In experiments presented in Specific Aim 3 we will study mice that are deficient in ceruloplasmin (Cp) and hephaestin (Heph), ferroxidase proteins that convert ferrous (Fe2+) to ferric (Fe3+) iron so as to promote cellular iron export. Effects on the phenotype of the Cp-/-;Heph-/- mouse will be assessed when an inhibitor of bisretinoid formation is administered; in Abca4-/-; Cp-/-;Heph-/- mice which will have high levels of both iron and bisretinoids in the RPE, and when no RPE bisretinoid (Rpe6rd12) and deficiency in Cp-/-;Heph-/- are combined in Rpe6rd12; Cp-/-;Heph-/- mice. Completion of this research will advance our understanding of how, iron, light and bisretinoids combine to contribute to disease processes in age-related and monogenic retinal disorders.

视网膜色素上皮（RPE）细胞随着年龄的增长积累铁，并在威胁视力的疾病中，年龄相关性黄斑变性（AMD）、隐性Stargardt病（STGD 1）和浆细胞胞浆蛋白血症。不受约束的游离铁可导致氧化还原失衡，这是由于铁催化形成高活性羟基过氧化氢的自由基RPE所承受的氧化负荷也来源于视黄酸去加合物（bisretinoids）的混合物，随着年龄的增长以脂褐素的形式积累。的破坏性影响 RPE细胞上的这些化合物涉及许多与年龄相关的和早发性形式的视网膜色素变性。疾病包括STGD 1和AMD。这些色素的不良影响可能至少部分是由于它们光生活性氧物质和光降解成破坏性二羰基和有碎片。拟议研究的主要目标是了解铁是否可以与RPE中的双视黄酸相互作用以促进RPE细胞损伤和死亡。这个问题的核心假设是一种观点认为，失调的细胞内铁介导的不良反应部分是通过促进bisretinoid 氧化和降解。如果氧化还原失衡是由铁和双维甲酸的组合增强光氧化，铁螯合作用可能是视网膜保护性的疾病，涉及双视黄酸毒性，包括 STGD 1.在具体目标1中，我们将确定去铁酮（DFP）治疗对Abca 4-/-小鼠的影响。DFP 是临床上重要的铁螯合剂，用于降低铁水平。使用DFP，我们将测试保护对抗铁介导的双视黄酸氧化和Abca 4-/-小鼠的感光细胞损失。氧化应激将使用一组氧化还原指示剂进行评估，并将采用基于细胞的和无细胞的测定。在特定目的2，我们建议确定补充铁是否有助于光氧化/氧化，双视黄酸的降解。这一目标将通过小鼠、细胞和无细胞试验来实现。我们会查明铁介导毒性的途径之一是否是通过促进双视黄酸氧化。我们还将确定在Abca 4-/-小鼠（STGD 1模型）中细胞内铁是否升高。在实验中，具体目标3我们将研究缺乏铜蓝蛋白（Cp）和肝啡肽（Heph），铁氧化酶将亚铁（Fe 2+）转化为三价铁（Fe 3+）以促进细胞铁输出的蛋白质。效应对当双视黄酸形成的抑制剂被施用时，将评估Cp-/-;Heph-/-小鼠的表型。在RPE中具有高水平铁和双类视色素的Abca 4-/-; Cp-/-;Heph-/-小鼠中，当没有RPE双视黄酸（Rpe 6 rd 12）和Cp-/-;Heph-/-缺陷合并Rpe 6 rd 12; Cp-/-;Heph-/-时，小鼠这项研究的完成将推进我们对铁、光和双维甲酸联合收割机如何结合的理解有助于年龄相关性和单基因视网膜疾病的疾病过程。