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Regulation of RPE degeneration by REV-ERBalpha

REV-ERBalpha 对 RPE 变性的调节

基本信息

批准号：
10667553
负责人：
JING CHEN
金额：
$ 53.32万
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/10667553
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 Cytoprotection DNA Data Deposition Development Disease Disease model Electroretinography Environment Event 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 Lesion Ligands Light Link Lipids LoxP-flanked allele 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 Photoreceptors Process Reactive Oxygen Species Regulation Rejuvenation 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 behavioral response catalase circadian circadian pacemaker design improved in vivo lipid metabolism mouse model novel novel strategies nuclear factor-erythroid 2 oxidation oxidative damage pharmacologic preservation prevent protective effect public health relevance response retinal toxicity 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.

项目概要视网膜色素上皮 (RPE) 变性导致年龄相关性黄斑变性导致视力丧失（AMD）和色素性视网膜炎（RP）。促进 RPE（以及光感受器）的存活对于保护视力。然而许多因素导致眼部疾病中 RPE 变性，包括遗传和环境因素，氧化应激是 RPE 功能障碍的主要原因之一变性，主要源自过量的线粒体氧化产物和吞噬作用相关的脂质氧化。然而，氧化应激失调导致 RPE 功能障碍和眼部疾病的退化仍未完全确定。此外，缺乏有效的方法促进 RPE 健康和生存。识别感知 RPE 氧化还原的基本分子连接（还原/氧化）环境影响 RPE 功能障碍和变性将有助于识别新的分子靶标可恢复衰老 RPE 中的内源性细胞防御系统并防止视力丧失在眼部疾病中。在这个项目中，我们鉴定了一种氧化还原感应核受体 REV-ERBα，它可能充当连接 RPE 氧化还原稳态和 RPE 抗氧化防御以影响 RPE 的转录调节因子退化。 REV-ERBα 作为氧化还原和配体依赖性转录因子发挥作用，控制多个生物过程，包括细胞代谢、炎症和昼夜节律。我们的初步结果表明：1）RPE 中 REV-ERBα 水平随着年龄的增长而下降； 2) 小鼠 REV-ERBα 基因缺失导致与年龄相关的 RPE 变性，伴有视网膜下沉积、视功能受损和 RPE 吞噬功能减弱； 3）RPE特异性缺失REV-ERBα导致类似的眼底病变； 4） REV-ERBα 缺乏会加剧体内和体内化学诱导的 RPE 损伤和视网膜毒性体外； 4) REV-ERBα的激活在体外和体内保护RPE； 5) REV-ERBα直接调节核红细胞 2 因子相关因子 2 (NRF2) 转录及其相关抗氧化基因。我们假设 REV-ERBα 是 RPE 细胞内抗氧化防御系统的新型氧化还原敏感调节剂，并且激活REV-ERBα是保护RPE的新方法。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 的药理学方法退化。从机制上讲，这项工作将探讨 REV-ERBα 是否保护 RPE 小瓶增强 RPE 抗氧化自卫。这项拟议的工作将揭示潜在的新分子调控机制 RPE 变性和新的可药物分子靶标，用于开发对抗 RPE 的改进策略眼部疾病的损伤和退化。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Oxidative stress in retinal pigment epithelium degeneration: from pathogenesis to therapeutic targets in dry age-related macular degeneration.

DOI：
10.4103/1673-5374.369098
发表时间：
2023-10
期刊：
Neural regeneration research
影响因子：
6.1
作者：
Maurya M;Bora K;Blomfield AK;Pavlovich MC;Huang S;Liu CH;Chen J
通讯作者：
Chen J

Oxidative Stress and Antioxidants in Age-Related Macular Degeneration.

DOI：
10.3390/antiox12071379
发表时间：
2023-07-03
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
0
作者：
通讯作者：

Assessment of Inner Blood-Retinal Barrier: Animal Models and Methods.

DOI：
10.3390/cells12202443
发表时间：
2023-10-12
期刊：
Cells
影响因子：
6
作者：
通讯作者：

Endothelial Cell Transcytosis Assay as an In Vitro Model to Evaluate Inner Blood-Retinal Barrier Permeability.

DOI：
10.3791/64076
发表时间：
2022-06-07
期刊：
Journal of visualized experiments : JoVE
影响因子：
0
作者：
Bora K;Wang Z;Yemanyi F;Maurya M;Blomfield AK;Tomita Y;Chen J
通讯作者：
Chen J

Amino acid transporter SLC38A5 regulates developmental and pathological retinal angiogenesis.

DOI：
10.7554/elife.73105
发表时间：
2022-12-01
期刊：
eLife
影响因子：
7.7
作者：
Wang Z;Yemanyi F;Blomfield AK;Bora K;Huang S;Liu CH;Britton WR;Cho SS;Tomita Y;Fu Z;Ma JX;Li WH;Chen J
通讯作者：
Chen J