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

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

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Bisretinoids: More than Meets the Eye.
双维A酸:不仅仅是表面上看到的。
Bisretinoid Photodegradation Is Likely Not a Good Thing.
双维A酸光降解可能不是一件好事。
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Janet Ruthe Sparrow其他文献

Janet Ruthe Sparrow的其他文献

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{{ truncateString('Janet Ruthe Sparrow', 18)}}的其他基金

Precision genome surgery in autologous stem cell transplant
自体干细胞移植中的精准基因组手术
  • 批准号:
    9811117
  • 财政年份:
    2019
  • 资助金额:
    $ 49.93万
  • 项目类别:
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
  • 批准号:
    10090468
  • 财政年份:
    2018
  • 资助金额:
    $ 49.93万
  • 项目类别:
Quantitative Fundus Autofluorescence in Retinal Disorders
视网膜疾病中的定量眼底自发荧光
  • 批准号:
    10358501
  • 财政年份:
    2014
  • 资助金额:
    $ 49.93万
  • 项目类别:
Quantitative Fundus Autofluorescence in Retinal Disorders
视网膜疾病中的定量眼底自发荧光
  • 批准号:
    8619402
  • 财政年份:
    2014
  • 资助金额:
    $ 49.93万
  • 项目类别:
Quantitative Fundus Autofluorescence in Retinal Disorders
视网膜疾病中的定量眼底自发荧光
  • 批准号:
    9084593
  • 财政年份:
    2014
  • 资助金额:
    $ 49.93万
  • 项目类别:
Imaging, Histology and Functional Diagnostics Core
影像、组织学和功能诊断核心
  • 批准号:
    10273969
  • 财政年份:
    2010
  • 资助金额:
    $ 49.93万
  • 项目类别:
Imaging, Histology and Functional Diagnostics Core
影像、组织学和功能诊断核心
  • 批准号:
    10475818
  • 财政年份:
    2010
  • 资助金额:
    $ 49.93万
  • 项目类别:
Imaging, Histology and Functional Diagnostics Core
影像、组织学和功能诊断核心
  • 批准号:
    10681428
  • 财政年份:
    2010
  • 资助金额:
    $ 49.93万
  • 项目类别:
IMPACT OF LIPOFUSCIN IN RETINAL PIGMENT EPITHELIAL CELLS
脂褐质对视网膜色素上皮细胞的影响
  • 批准号:
    6086563
  • 财政年份:
    2000
  • 资助金额:
    $ 49.93万
  • 项目类别:
Impact of Lipofuscin in Retinal Pigment Epithelial Cells
脂褐素对视网膜色素上皮细胞的影响
  • 批准号:
    7523804
  • 财政年份:
    2000
  • 资助金额:
    $ 49.93万
  • 项目类别:

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临床记录中缩写词的实时消歧
  • 批准号:
    8077875
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    2010
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    $ 49.93万
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  • 批准号:
    8589822
  • 财政年份:
    2010
  • 资助金额:
    $ 49.93万
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Real-time Disambiguation of Abbreviations in Clinical Notes
临床记录中缩写词的实时消歧
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    8305149
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