Nrf2 signaling and oxidative stress in age-related macular degeneration

年龄相关性黄斑变性中的 Nrf2 信号传导和氧化应激

• 批准号: 8792217
• 负责人: James T Handa
• 金额: $ 56.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792217
• 关键词: Address; Age related macular degeneration; Aging; Anaphylatoxins; Antioxidants; Biogenesis; Blindness; Bruch' s basal membrane structure; Cell Aging; Cell physiology; Cells; Chronic; Complement; Complement 3a; Development; Disease; Drusen; Elderly; Equilibrium; Event; Failure; Foundations; Free Radicals; Functional disorder; Funding; Generations; Genetic; Goals; Health; Homeostasis; Immune response; Inflammation; Inflammatory; Injury; Link; Mitochondria; Mus; Natural Immunity; Oxidative Stress; Pathologic; Patients; Phenotype; Physiological; Play; Prevention therapy; Production; Reaction; Reactive Oxygen Species; Recruitment Activity; Regulation; Research; Role; Signal Transduction; Smoking; Stimulus; Structure of retinal pigment epithelium; System; Testing; Tissues; Work; base; cell age; cell injury; cigarette smoke-induced; cigarette smoking; cigarette smoking; disorder risk; effective therapy; environmental tobacco smoke exposure; innovation; macrophage; mitochondrial dysfunction; oxidative damage; response; stressor; targeted treatment; therapy design; transcription factor

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly, yet patients with early disease are without therapy. To address this shortcoming, this proposal focuses on early disease. Two key events in early AMD are retinal pigment epithelial cell (RPE) dysfunction and drusen biogenesis. Inadequately neutralized reactive oxygen species (ROS) and dysregulated innate immunity interact together to play a pivotal role. Central to oxidative homeostasis, especially in mitochondria, is the Nrf2 transcription factor, which controls the most comprehensive antioxidant response system. Nrf2 signaling can become impaired with aging and/or smoking. The objective of this proposal to define how Nrf2 protects against RPE mitochondrial dysfunction and unregulated innate immunity. The hypothesis to be tested is that that impaired Nrf2 signaling induces mitochondrial and RPE dysfunction that results in an oxidative, inflammatory, and pathologic microenvironment. The proposed specific aims are: 1. Determine the extent that impaired Nrf2 signaling leads to un-neutralized mitochondrial ROS and RPE dysfunction with cigarette smoke exposure. Our hypothesis is that impaired Nrf2 signaling in the RPE from aging and chronic smoking reduces mitochondrial antioxidant defense resulting in inadequately neutralized ROS and RPE dysfunction. 2. Determine the extent that impaired Nrf2 signaling decreases mitophagy, and results in RPE dysfunction with cigarette smoke exposure. Our hypothesis is that impaired Nrf2 signaling in the RPE from aging and chronic smoking decreases mitophagy, cumulatively increasing the number of dysfunctional mitochondria and inadequately neutralized ROS, resulting in RPE dysfunction. 3. Determine the extent that impaired Nrf2 signaling disrupts regulation of innate immunity. Based on our work showing C3a and IL-1b generation by CS and Nrf2 deficiency, our hypothesis is that impaired Nrf2 signaling magnifies oxidative stress, which activates the inflammasome to promote a pro-inflammatory microenvironment with accumulation of macrophages with impaired function. These contributions are significant because they will establish Nrf2 as a treatment target for early AMD. The research is innovative since it will investigate understudied (decreased Nrf2 signaling on mitochondrial antioxidants and mitophagy), unresolved (inflammasome and macrophage function) and unique (the synergy of ROS and innate immunity) factors on RPE and macrophage function using unique, state-of-the- art genetic mice with fresh, but decisive factors that have not been previously tested. Macrophages will be studied from a new perspective that defines both phenotype and function since both are influenced by their surroundings. Our discovery of reduced Nrf2 with aging and CS, which generates C3a and IL-1b, a key substrate of the inflammasome, and the proposed studies, which will link complement with the inflammasome, macrophage function, and an AMD phenotype, is highly innovative. Targeted therapy that reinvigorates Nrf2 to maintain oxidative homeostasis and protective innate immunity is expected to result from this work.

描述（申请人提供）：年龄相关性黄斑变性（AMD）是老年人失明的主要原因，但早期疾病患者却得不到治疗。为了解决这一缺点，该提案重点关注早期疾病。早期 AMD 的两个关键事件是视网膜色素上皮细胞 (RPE) 功能障碍和玻璃疣生物发生。活性氧 (ROS) 中和不足和先天免疫失调相互作用，发挥着关键作用。 Nrf2 转录因子是氧化稳态的核心，尤其是在线粒体中，它控制着最全面的抗氧化反应系统。 Nrf2 信号传导可能会因衰老和/或吸烟而受损。该提案的目的是定义 Nrf2 如何防止 RPE 线粒体功能障碍和不受调节的先天免疫。 待检验的假设是，受损的 Nrf2 信号传导会诱导线粒体和 RPE 功能障碍，从而导致氧化、炎症和病理性微环境。拟议的具体目标是： 1. 确定 Nrf2 信号传导受损导致香烟烟雾暴露导致未中和的线粒体 ROS 和 RPE 功能障碍的程度。我们的假设是，由于衰老和长期吸烟，RPE 中的 Nrf2 信号受损会降低线粒体抗氧化防御，导致 ROS 中和不足和 RPE 功能障碍。 2. 确定受损的 Nrf2 信号传导会降低线粒体自噬的程度，并导致暴露于香烟烟雾时导致 RPE 功能障碍。我们的假设是，衰老和长期吸烟导致 RPE 中的 Nrf2 信号受损会减少线粒体自噬，从而累积增加功能失调的线粒体数量和中和不充分的 ROS，从而导致 RPE 功能障碍。 3. 确定受损的 Nrf2 信号传导破坏先天免疫调节的程度。基于我们的研究表明，CS 和 Nrf2 缺陷会产生 C3a 和 IL-1b，我们的假设是，受损的 Nrf2 信号传导会放大氧化应激，从而激活炎症小体，促进促炎微环境，从而导致功能受损的巨噬细胞积聚。这些贡献意义重大，因为它们将把 Nrf2 确立为早期 AMD 的治疗靶点。该研究具有创新性，因为它将利用独特的最新研究成果来研究尚未解决的因素（线粒体抗氧化剂和线粒体自噬的 Nrf2 信号减弱）、尚未解决的因素（炎症小体和巨噬细胞功能）以及独特的因素（ROS 和先天免疫的协同作用）对 RPE 和巨噬细胞功能的影响。 -最先进的基因小鼠，具有以前未测试过的新鲜但决定性的因素。巨噬细胞将从定义表型和功能的新角度进行研究，因为两者都受到周围环境的影响。我们发现 Nrf2 会随着衰老和 CS 减少，从而产生 C3a 和 IL-1b（炎症小体的关键底物），并且拟议的研究将补体与炎症小体、巨噬细胞功能和 AMD 表型联系起来，具有高度创新性。这项工作有望实现重振 Nrf2 以维持氧化稳态和保护性先天免疫的靶向治疗。