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
• 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
• 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' 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

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）：拟议的研究项目努力推进我们对脂褐素在视网膜色素上皮细胞（RPE）中积累有助于萎缩性黄斑变性疾病过程的机制的理解，包括年龄相关和青少年（Stargardt病和Best卵黄样黄斑营养不良）形式。RPE细胞的脂褐素主要来源于感光细胞，在很大程度上是由全反式视网膜反应产生的，当视觉色素吸收光子时形成。为了实现我们的目标，我们将使用细胞培养、体外实验和小鼠模型进行实验。鉴于将年龄相关性黄斑变性（AMD）与炎症过程联系起来的遗传学发现，我们将研究双维甲酸RPE脂褐素色素的光氧化产物作为补体的激活剂，补体是免疫途径的一个元素（Aim 1）。这些研究提出了与AMD相关的四个因素：炎症、氧化损伤、dren和RPE脂褐素。我们还将比较已知的脂褐素成分在光生成活性氧和光诱导裂解方面的倾向（目的2）。在与最佳卵黄样黄斑营养不良和其他VMD2相关疾病相关的研究中，我们将探索VMD2蛋白产物bestrophin-1功能障碍改变细胞内氯离子电导的假设，从而改变ph依赖性光氧化速率以及RPE脂褐素全反式视网膜二聚体系列质子化/偶联和非质子化/非偶联形式之间的平衡。我们提出，平衡的转变有利于RPE脂褐素成分（非共轭的全反式视网膜二聚体），它是含醛的，更具有光反应性（目的3）。公共卫生相关性：国家眼科研究所的5年计划目标是提高对黄斑变性的分子和生化基础的理解。AMD在美国影响了超过175万人。以1/10,000的患病率计算，另有30,000美国人患有Stargardt病。由于人口老龄化的趋势，到2020年AMD的病例数可能会增加到300万。更深入地了解单个RPE脂褐素色素的特性和特性、它们的不良行为和影响它们形成的因素，将有助于出现新的治疗方法，以减少脂褐素的积累和/或中和其影响，从而减少黄斑变性的发病率和进展。