Regulation of RPE degeneration by REV-ERBalpha

REV-ERBalpha 对 RPE 变性的调节

基本信息

批准号：
10448503
负责人：
JING CHEN
金额：
$ 51.72万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10448503
关键词：
Acute Acute Disease Affect Age related macular degeneration Aging Agonist Antioxidants Atrophic Binding Biological Process Blindness Cell Culture Techniques Cell physiology Chemicals Chronic Chronic Disease Circadian Rhythms Complement Complex DNA Data Deposition Development Disease Disease model Electroretinography Environment Eye Eye diseases Family Functional disorder Fundus Gene Expression Genes Genetic Genetic Transcription Goals Health Heme Homeostasis Immune System Diseases Impairment In Vitro Inflammation Inflammatory Inherited Knock-out Knockout Mice Lead Lesion Ligands Link Lipids Lung Mediating Metabolic Metabolism Mitochondria Modeling Molecular Molecular Target Morphology Mus Mutant Strains Mice Neonatal Nuclear Receptors Nucleic Acid Regulatory Sequences Oxidants Oxidation-Reduction Oxidative Stress Pathway interactions Phagocytes Phagocytosis Pharmacology Photoreceptors Process Reactive Oxygen Species Regulation Retina Retinal Degeneration Retinitis Pigmentosa Role Signal Transduction Structure of retinal pigment epithelium System Testing Tissues Toxic effect Transcriptional Regulation Vial device Vision Visual impairment Work age related aged antagonist antioxidant enzyme base behavioral response catalase circadian design improved in vivo mouse model novel novel strategies nuclear factor-erythroid 2 oxidation oxidative damage preservation prevent protective effect public health relevance sensor sodium iodate superoxide dismutase 1 transcription factor transcriptome sequencing visual processing

项目摘要

Project Summary Degeneration of retinal pigment epithelium (RPE) causes vision loss in age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Promoting survival of RPE (and thereby photoreceptors) is critical for preserving vision. Whereas many factors contribute to RPE degeneration in eye diseases including both genetic and environmental ones, oxidative stress is one of the major contributors to RPE dysfunction and degeneration, derived primarily from excess mitochondrial oxidative products, and phagocytosis-related lipid oxidation. However, the processes through which dysregulated oxidative stress leads to RPE dysfunction and degeneration in eye diseases remain incompletely defined. Moreover, there is lack of effective approaches to promote RPE health and survival. Identification of the basic molecular links which sense RPE redox (reduction/oxidation) environment to impact RPE dysfunction and degeneration will aid in the identification of new molecular targets to rejuvenate endogenous cellular defense system in aging RPE and prevent vision loss in eye diseases. In this project we identified a redox-sensing nuclear receptor REV-ERBα, which may act as a transcriptional regulator linking RPE redox homeostasis and RPE antioxidant defense to impact RPE degeneration. REV-ERBα, functioning as a redox- and ligand-dependent transcription factor, controls multiple biological processes including cellular metabolism, inflammation, and circadian rhythm. Our preliminary results show that: 1) REV-ERBα levels decline with aging in RPE; 2) genetic deletion of REV-ERBα in mice leads to age-related development of RPE degeneration, with subretinal deposits, impaired visual function and dampened RPE phagocytic function; 3) RPE specific deletion of REV-ERBα causes similar fundus lesions; 4) REV-ERBα deficiency exacerbates chemically-induced induced RPE damage and retinal toxicity in vivo and in vitro; 4) activation of REV-ERBα protects RPE in vitro and in vivo; and 5) REV-ERBα directly regulates nuclear factor erythroid-2 related factor 2 (NRF2) transcription and its associated antioxidant genes. We hypothesize that REV-ERBα is a novel redox-sensitive regulator of RPE intracellular antioxidant defense system, and activating REV-ERBα is a new way to protect RPE. This hypothesis will be evaluated with both genetic and pharmacological approaches of modulating REV-ERBα in both acute and chronic models of RPE damage and degeneration. Mechanistically this work will explore whether REV-ERBα protects RPE vial enhancing RPE antioxidant self-defense. This proposed work will uncover novel molecular regulatory mechanisms underlying RPE degeneration, and new druggable molecular targets for developing improved strategies to counter RPE damage and degeneration in eye diseases.

项目摘要视网膜色素上皮（RPE）的变性会导致与年龄相关的黄斑变性的视力丧失（AMD）和色素性视网膜炎（RP）。促进RPE的生存（及其受感受器）对于保持视野。而许多因素导致眼部疾病的RPE变性，包括遗传和环境的氧化应激是导致RPE功能障碍和的主要因素之一退化，主要是从多余的线粒体氧化产物中得出的，以及与吞噬相关的脂质氧化。但是，氧化应激导致RPE功能障碍的过程和眼病的变性仍未完全定义。而且，缺乏有效的方法促进RPE健康和生存。鉴定基本分子链接，感知RPE氧化还原（还原/氧化）影响RPE功能障碍和变性的环境将有助于识别新的分子靶标在衰老的RPE中恢复内源性细胞防御系统并防止视力丧失在这个项目中，我们确定了一种氧化还原核接收器Rev-ERBα，可以充当连接RPE氧化还原稳态和RPE抗氧化防御的转录调节器影响RPE 退化。 Rev-ERBα充当氧化还原和配体依赖性转录因子，控制多个生物学过程，包括细胞代谢，感染和昼夜节律。我们的初步结果证明：1）REV-ERBα水平随着RPE的衰老而下降； 2）小鼠Rev-erbα的遗传缺失导致 RPE变性与年龄相关的发展，视网膜下沉积，视觉功能受损和衰减的RPE吞噬功能； 3）REV-ERBα的RPE特异性缺失会导致类似的眼底病变； 4） Rev-erbα缺乏加剧了化学诱导的RPE损伤和体内和在体内的视网膜毒性体外4）Rev-ERBα的激活在体外和体内保护RPE； 5）Rev-ERBα直接调节核因子红细胞-2相关因子2（NRF2）转录及其相关的抗氧化剂基因。我们假设 Rev-ERBα是RPE细胞内抗氧化剂防御系统的新型氧化还原敏感剂，并且激活Rev-ERBα是保护RPE的一种新方法。该假设将通过遗传和在RPE损伤的急性和慢性模型中调节Rev-ERBα的药理方法退化。从机械上讲，这项工作将探索Rev-ERBα是否保护RPE小瓶增强RPE 抗氧化自卫。这项提出的工作将发现新的分子调节机制 RPE变性和新的可药物分子靶标，用于制定改进的策略以对抗RPE 眼病的损害和变性。