RORalpha mediates chronic subretinal inflammation associated with AMD

RORalpha 介导与 AMD 相关的慢性视网膜下炎症

基本信息

批准号：
10625419
负责人：
JING CHEN
金额：
$ 50.77万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-02 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625419
关键词：
Acceleration Acute Affect Age related macular degeneration Aging Agonist Blindness Cholesterol Cholesterol Homeostasis Choroid Choroidal Neovascularization Chronic Clinical Complement Complement Activation Complement Factor H Complex Cytoprotection Data Deposition Disease Drusen Dryness Elderly Eye Eye diseases Fundus Genes Genetic Transcription Genetic Variation Goals Grant Health Hepatocyte High Fat Diet Histology Homeostasis Human Human Genetics Immune Immunity In Vitro Inflammation Inflammatory Lesion Ligands Light Link Lipids Liver LoxP-flanked allele Macrophage Mediating Metabolic Metabolism Microglia Modeling Morphology Mus Myelogenous Natural Immunity Neurodegenerative Disorders Nonexudative age-related macular degeneration Nuclear Receptors Orphan PPAR gamma Pathogenicity Pathologic Pathway interactions Photoreceptors Production Proliferating Proteins Retina Retinal Degeneration Retinoic Acid Receptor Risk Role Structure of retinal pigment epithelium Susceptibility Gene Testing Thinness Transcriptional Regulation Vision Wild Type Mouse Work age related chemokine cholesterol trafficking design human data in vivo inflammatory marker lipid biosynthesis lipid mediator mouse model neovascular novel strategies overexpression prevent public health relevance receptor recruit retinal damage transcription factor uptake

项目摘要

Project Summary Age-related macular degeneration (AMD) is a major cause of blindness in the elderly, associated with altered lipid (cholesterol) metabolism and altered immunity (complement). Chronic subretinal inflammation occurs during aging in clinical and experimental AMD, and is associated many other neurodegenerative diseases. Resolving harmful persistent inflammation is important to protect the retinas from age-related damage. Previous work identified that retinoic-acid-receptor-related orphan receptor alpha (RORαa lipid (cholesterol)-sensing nuclear receptor, is genetically linked with the risk for wet AMD. RORαis a transcription factor that regulates lipid homeostasis and inflammation, both important for AMD. Our preliminary results from mouse models of aging and retinal degeneration indicate that: 1) RORα deficiency induces subretinal deposits, accumulation of lipid- enriched microglia/macrophages in the subretinal space in aging mice; 2) RORα deficiency worsens light- induced retinal degeneration; 3) Loss of RORα induces microglia/macrophage lipogenesis and chronic inflammation in RPE/choroid with induction of PPARγ, a key lipid metabolic regulator; 4) RORα deficiency alters complement factors and suppresses complement inhibitory factor H (CFH, one of the strongest AMD susceptibility genes) in the liver and in the eyes; and 5) RORα directly regulates both CFH and PPARγ transcription. Based on these findings, we hypothesize that during aging, RORα links lipid dysregulation with subretinal microglia/macrophage lipogenesis and complement alteration, to suppress chronic pathogenic subretinal inflammation; RORα activation may resolve chronic inflammation associated with early AMD. We will test this hypothesis with three aims. Aim I: To determine whether RORα deficiency exacerbates pathological subretinal inflammation and retinal degeneration in RORα deficient mice during aging and with a light-induced retinal degeneration model. Aim II: To assess if RORα deficiency induces chronic subretinal inflammation by accelerating microglia/macrophage recruitment, lipogenesis, and function through PPARγ, and/or by controlling systemic and/or local CFH function and complement cascade. Aim III: to determine if RORα activation resolves chronic inflammation and protects the retinas in chronic dry AMD models and in light-induced retinal degeneration model. This work will uncover the potential role of RORα as a key mediator of lipid homeostasis and altered innate immunity in chronic subretinal inflammation associated with AMD, and develop potential new treatments via activating RORα to resolve persistent inflammation during aging and protect retinas.

项目概要年龄相关性黄斑变性（AMD）是老年人失明的主要原因，与黄斑变性有关脂质（胆固醇）代谢和免疫力改变（补体）发生在慢性视网膜下炎症期间。临床和实验性 AMD 中的衰老与许多其他神经退行性疾病有关。有害的持续炎症对于保护视网膜免受与年龄相关的损伤很重要。确定了视黄酸受体相关的孤儿受体 α（RORα一种脂质（胆固醇）感应核） RORα 受体与湿性 AMD 风险具有遗传相关性，RORα 是调节脂质的转录因子。体内平衡和炎症对 AMD 都很重要，我们的初步结果来自小鼠衰老模型。视网膜变性表明：1) RORα 会导致视网膜下沉积物缺乏，脂质沉积衰老小鼠视网膜下腔中小胶质细胞/巨噬细胞富集；2) RORα 缺乏使光- 诱导视网膜变性；3) RORα 缺失诱导小胶质细胞/巨噬细胞脂肪生成和慢性诱导 PPARγ（一种关键的脂质代谢调节剂）引起 RPE/脉络膜炎症；4) RORα 缺乏会改变；因子并抑制补体抑制因子 H（CFH，最强的 AMD 因子之一）易感基因）在肝脏和眼睛中；5）RORα直接调节CFH和PPARγ 基于这些发现，我们发现在衰老过程中，RORα 与脂质失调有关。视网膜下小胶质细胞/巨噬细胞脂肪生成和补体改变，以抑制慢性致病性视网膜下炎症；RORα 激活可能会解决与早期 AMD 相关的慢性炎症。通过三个目标检验这一假设：确定 RORα 缺乏是否会导致病理恶化。 RORα 缺陷小鼠在衰老过程中和光诱导下的视网膜下炎症和视网膜变性目标 II：评估 RORα 缺陷是否会诱发慢性视网膜下炎症。通过 PPARγ 加速小胶质细胞/巨噬细胞的募集、脂肪生成和功能，和/或通过控制全身和/或局部 CFH 功能和补体级联反应目标 III：确定 RORα 激活是否得到解决。在慢性干性 AMD 模型和光诱导视网膜中抑制慢性炎症并保护视网膜这项工作将揭示 RORα 作为脂质稳态关键介质的潜在作用。并改变与 AMD 相关的慢性视网膜下炎症的先天免疫，并开发潜在的新产品通过激活 RORα 来解决衰老过程中持续的炎症并保护视网膜。