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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：
10402760
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10402760
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 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.

视网膜色素上皮细胞（RPE）随着年龄的增长而积累铁，在威胁视力的疾病中，包括