Impact of Lipofuscin in Retinal Pigment Epithelial Cells

脂褐素对视网膜色素上皮细胞的影响

基本信息

批准号：
7523804
负责人：
Janet Ruthe Sparrow
金额：
$ 40.08万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-05-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7523804
关键词：
ATP-Binding Cassette Transporters Abbreviations Address Adolescent Adult Affect Age Age related macular degeneration Aldehydes All-Trans-Retinol American Area Atrophic Behavior Biochemical C-reactive protein Cells Chloride Ion Chlorides Complement Complement Activation Complement Factor B Complement Factor H Cultured Cells Deposition Disease Drusen Elements Enzyme Immunoassay Epithelial Equilibrium Ethanolamines Event Figs - dietary Fundus Generations Genes Genetic Goals High Pressure Liquid Chromatography Immune Incidence Individual Inflammation Inflammatory Investigation Ions Lead Light Link Lipofuscin Localized Macular degeneration Mass Spectrum Analysis Measures Molecular Monitor Mutation National Eye Institute Nonexudative age-related macular degeneration Nuclear Magnetic Resonance Numbers Oxygen Pathway interactions Patients Phagocytosis Phosphate Buffer Phosphatidylethanolamine Photons Photoreceptors Pigments Predisposition Prevalence Process Property Proteins Public Health Rate Reaction Reporting Research Retina Retinal Retinal Diseases Retinal Pigments Retinoids Saline Schiff Bases Series Site Spectrometry, Mass, Electrospray Ionization Spectrometry, Mass, Fast Atom Bombardment Stargardt&apos s disease Structure Structure of retinal pigment epithelium Testing United States Vitelliform macular dystrophy Work age related aging population base cysteine rich protein deprotonation dimer disease-causing mutation ethanolamine improved in vitro Assay in vitro Model in vivo insight interest liquid chromatography mass spectrometry macular dystrophy mouse model novel therapeutics phosphatidylethanolamine programs protonation research study trend visual cycle

项目摘要

DESCRIPTION (provided by applicant): The proposed research program endeavors to advance our understanding of the mechanisms by which the lipofuscin that accumulates in retinal pigment epithelial cells (RPE) contributes to disease processes in atrophic macular degeneration, including age-related and juvenile (Stargardt disease and Best vitelliform macular dystrophy) forms. The lipofuscin of RPE cells originates primarily in photoreceptor cells and is generated, in large part, from reactions of all-trans-retinal, which forms when visual pigment absorbs photons of light. To achieve our objectives, we will conduct experiments using cell culture, in vitro assays and mouse models. In light of genetic discoveries linking age-related macular degeneration (AMD) to inflammatory processes, we will investigate photooxidation products of bisretinoid RPE lipofuscin pigments as activators of complement, an element of immune pathways (Aim 1). These studies address four factors posited as being associated with AMD: inflammation, oxidative damage, drusen and RPE lipofuscin. We will also compare known lipofuscin constituents in terms of their propensity for photo-generating reactive forms of oxygen and for photo-induced cleavage (Aim 2). In studies related to Best vitelliform macular dystrophy and other VMD2-associated disorders, we will explore the hypothesis that dysfunctioning of bestrophin-1, the protein product of VMD2, alters intracellular chloride conductances thereby changing pH-dependent rates of photooxidation and equilibria between protonated/conjugated and unprotonated/unconjugated forms of the all-trans-retinal dimer series of RPE lipofuscin pigments. We propose that the shift in equilibrium favors an RPE lipofuscin constituent (unconjugated all-trans-retinal dimer) that is aldehyde-bearing and more photoreactive (Aim 3). PUBLIC HEALTH RELEVANCE: The National Eye Institute has as a 5-year program goal, improved understanding of the molecular and biochemical basis of macular degeneration. AMD affects more than 1.75 million people in the United States. Based on a prevalence of 1/10,000, an additional 30,000 Americans are afflicted with Stargardt disease. Due to the trend toward population aging, the number of cases of AMD could increase to 3 million by 2020. Greater insight into the identities and properties of individual RPE lipofuscin pigments, their adverse behaviors and the factors that influence their formation will facilitate the emergence of novel therapeutic approaches to minimize lipofuscin accumulation and/or neutralize its impact, and thus reduce the incidence and progression of macular degeneration.

描述（由申请人提供）：拟议的研究计划努力促进我们对视网膜色素上皮细胞中积累的脂肪霉素（RPE）的理解，从而有助于疾病的疾病过程，包括萎缩性黄斑变性的过程，包括年龄相关的和少数幼年（包括Stargardt疾病和最佳vitellifter Maculor Macuarliform Maculor Dystrophy）。 RPE细胞的脂肪霉素主要起源于感光细胞，在很大程度上是由全反视网膜反应产生的，当视觉色素吸收光子光子时，它们形成。为了实现我们的目标，我们将使用细胞培养，体外测定和小鼠模型进行实验。鉴于将与年龄相关的黄斑变性（AMD）与炎症过程联系起来的遗传发现，我们将研究双糖素RPE脂肪霉素色素的光氧化产物作为补体的激活剂，是免疫途径的元素（AIM 1）。这些研究介绍了与AMD相关的四个因素：炎症，氧化损伤，drusen和RPE脂肪霉素。我们还将根据其对氧的产生反应性形式和光诱导的裂解的倾向来比较已知的脂肪霉素成分（AIM 2）。 In studies related to Best vitelliform macular dystrophy and other VMD2-associated disorders, we will explore the hypothesis that dysfunctioning of bestrophin-1, the protein product of VMD2, alters intracellular chloride conductances thereby changing pH-dependent rates of photooxidation and equilibria between protonated/conjugated and unprotonated/unconjugated forms of the RPE脂肪霉素色素的全反视网膜二聚体系列。我们提出，平衡的变化有利于含醛的RPE脂肪霉素成分（未缀合的全反视网膜二聚体），该二二聚体是醛含量和更多的光电反应性（AIM 3）。公共卫生相关性：国家眼科研究所的目标是5年的目标，对黄斑变性的分子和生化基础有了改进的了解。在美国，AMD影响超过175万人。基于1/10,000的患病率，另外30,000名美国人患有Stargardt病。由于人口衰老的趋势，到2020年，AMD病例的数量可能会增加到300万。更深入地了解单个RPE脂肪霉素色素的身份和特性，它们的不良行为以及影响其形成的因素将促进新的治疗方法的出现，从而最大程度地减少脂肪蛋白的积累和中性效果，从而减少其影响。