RORalpha mediates chronic subretinal inflammation associated with AMD

项目摘要 老年性黄斑变性(AMD)是老年人致盲的主要原因，与黄斑变性有关 脂(胆固醇)代谢和免疫(补体)改变。慢性视网膜下炎症发生在 衰老在临床和实验性AMD中存在，并与许多其他神经退行性疾病有关。解析 有害的持续性炎症对于保护视网膜免受年龄相关性损害非常重要。以前的工作 发现维甲酸受体相关的孤儿受体α(RoRα)是一种脂质(胆固醇)敏感核 受体，在基因上与湿性AMD的风险有关。RoRα是一种调节脂质的转录因子 动态平衡和炎症对AMD都很重要。小鼠衰老模型的初步研究结果 视网膜退行性变提示：1)RoRα缺乏可导致视网膜下沉积、脂质堆积、视网膜色素沉着。 衰老小鼠视网膜下腔小胶质细胞/巨噬细胞增多；2)RORα缺乏症加重光损伤 3)RoRα缺失诱导小胶质细胞/巨噬细胞脂肪生成和慢性 视网膜色素上皮/脉络膜炎症与PPARγ的诱导有关；4)RoRα缺乏症改变 补体因子和抑制补体抑制因子H(CFH)，最强的AMD之一 易感基因)；5)RoRα直接调节CFH和PPARγ 抄写。基于这些发现，我们假设在衰老过程中，RoRα将血脂失调与 视网膜下小胶质细胞/巨噬细胞脂肪生成和补体改变，抑制慢性致病 视网膜下炎症；激活RoRα可以缓解与早期AMD相关的慢性炎症。我们会 用三个目标来检验这一假设。目的I：确定RoRα缺乏是否会加剧病理 RoR-α基因缺陷小鼠衰老和光照诱导的视网膜下炎症和视网膜变性 视网膜变性模型。目的II：评估RORα缺陷是否通过以下途径引起慢性视网膜下炎症 通过PPARγ和/或通过控制小胶质细胞/巨噬细胞募集、脂肪生成和功能 全身和/或局部CFH功能和补体级联。目的三：确定RoRα激活是否可解决 慢性干性AMD模型和光诱导视网膜的慢性炎症和保护作用 退化模型。这项工作将揭示RoRα作为脂质稳态的关键介体的潜在作用 并改变与AMD相关的慢性视网膜下炎症的天然免疫功能，并开发潜在的新的 通过激活RoRα来解决老化过程中的持续性炎症和保护视网膜的治疗。

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.