权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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(RPE)细胞随着年龄的增长积累铁，在威胁视力的疾病中，包括老年性黄斑变性(AMD)、隐性Stargardt病(STGD1)和无纤维蛋白溶酶血症。游离铁可导致氧化还原失衡，这是因为铁催化形成高活性羟基。过氧化氢产生的自由基。RPE所承受的氧化负担也源于一种随年龄增加的视黄醛加合物(双维A酸类)的混合物，形成脂褐素。它的破坏性影响 RPE细胞上的这些化合物与许多与年龄相关的和早发性视网膜有关疾病包括STGD1和AMD。这些色素的不良影响可能至少部分归因于它们的光生活性氧物种和光降解为有害的二羰基和含醛碎片。这项拟议研究的广泛目标是了解铁是否可以与RPE中的双维甲酸相互作用，促进RPE细胞的损伤和死亡。这一点的中心假设是该理论认为，细胞内铁的失调部分通过促进双维A酸类药物来调节不良反应。氧化和降解。如果铁和双维甲酸的组合或铁和双维A酸类化合物加剧了氧化还原失衡在涉及双维A酸类毒性的疾病中，光氧化、铁络合可能对视网膜具有保护作用，包括 STGD1.在具体目标1中，我们将确定去铁酮(DFP)对ABCA4-/-小鼠的治疗效果。DFP 是一种临床上重要的铁络合剂，可以降低铁的水平。使用DFP，我们将测试保护抗铁介导的双维A酸氧化和ABCA4-/-小鼠感光细胞丢失。氧化应激会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分析。具体而言目的2，我们建议确定补充铁是否有助于光氧化/氧化和双维A酸类化合物的降解。这一目标将通过使用小鼠、细胞和无细胞检测来实现。我们会确定铁介导毒性的途径之一是否是通过促进双维A酸氧化。我们还将确定STGD1模型ABCA4-/-小鼠细胞内铁是否升高。在中介绍的实验中具体目标3我们将研究铜蓝蛋白(CP)和肝素(Heph)、亚铁氧合酶缺乏的小鼠将亚铁(Fe2+)转化为铁(Fe3+)以促进细胞铁输出的蛋白质。对环境的影响当双维A酸类形成的抑制剂被用来评估CP-/-；Heph-/-小鼠的表型时给药；在ABCA4-/-；CP-/-；Heph-/-小鼠中，RPE中铁和双维A酸类化合物含量都很高，当没有RPE双维A酸类(Rpe6rd12)和缺乏CP-/-；Heph-/-时，Rpe6rd12；Cp-/-；老鼠。这项研究的完成将促进我们对铁、光和双维A酸类化合物如何结合的理解在年龄相关和单基因视网膜疾病的疾病过程中做出贡献。