Role of complement receptors and microglia in age-related macular degeneration

补体受体和小胶质细胞在年龄相关性黄斑变性中的作用

• 批准号: 268718306
• 负责人: Professor Dr. Thomas Langmann
• 金额: --
• 依托单位: Zentrum für Augenheilkunde
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/268718306?language=en
• 关键词: Role; complement; receptors; microglia; age

Age-related macular degeneration (AMD) is a leading cause of blindness in industrialized countries. Early AMD manifests as drusen deposits between the outer retina and the pigment epithelium. AMD can progress to late stage forms including choroidal neovascularization (CNV) and an atrophic form with macular degeneration of photoreceptors and the pigment epithelium. The etiology of AMD is not completely understood. However, genetic association studies in large patient cohorts and in situ analyses in AMD eyes as well as animal models mimicking some features of AMD have identified an important contribution of dysregulated innate immunity in the eye. Our project of the first funding period of FOR2240 has revealed local dysregulation of complement factors in ocular fluids of AMD patients and found a correlation of disease progression with hyperreflective foci (HF) as potential imaging markers for retinal immune cells. Furthermore, using a light damage paradigm and laser-triggered CNV in mice we established a comprehensive analysis of microglia and macrophages in the retina. Resident microglia-specific targeting of key immune pathways and immunomodulatory compounds could elucidate a vicious cycle of microglia reactivity, retinal degeneration and neoangiogenesis. These findings together provide evidence for an interaction of reactive microglia with aberrant complement proteins in the pathogenesis of AMD. However, the underlying mechanisms that link both systems are only incompletely explored. In this follow-up project we postulate that particularly the anaphylatoxin complement cleavage products C3a and C5a sustain chronic microglia reactivity via receptor-mediated recruitment and activation. We further postulate that hyperreflective foci could potentially mirror complement-regulated microglia responses and may therefore be used to monitor disease development in AMD patients and animal models. The project is subdivided into four specific aims in which we will determined the impact of C3a/C5a anaphylatoxins on microglia in vitro, test the effects of microglial C3a/C5a receptor deficiency in the laser-CNV and light damage models, evaluate the expression and localization of C3aR/C5aR in human retinal sections, and finally correlate the dynamics of hyperreflective foci with ocular complement factors in AMD patients and controls. The results of these studies will provide new insights into the immune-related etiology of AMD and may foster the development of novel effective treatments.

与年龄相关的黄斑变性（AMD）是工业化国家失明的主要原因。早期AMD表现为视网膜外部和色素上皮之间的drusen沉积物。 AMD可以发展为后期形式，包括脉络膜新生血管形成（CNV）和萎缩形式，具有黄斑的光感受器变性和色素上皮。 AMD的病因尚未完全理解。然而，在大型患者队列和AMD眼睛的原位分析以及模仿AMD某些特征的动物模型中进行的遗传关联研究已经确定了眼睛中先天免疫失调的重要贡献。我们在2240的第一个资金期间的项目表明，AMD患者的眼部流体中补体因子的局部失调，发现疾病进展与过度反射灶（HF）的相关性是视网膜免疫细胞的潜在成像标记。此外，在小鼠中使用轻损伤范式和激光触发的CNV，我们对视网膜中的小胶质细胞和巨噬细胞进行了全面的分析。驻留的小胶质细胞特异性靶向关键免疫途径和免疫调节化合物可以阐明小胶质细胞反应性，视网膜退化和新血管生成的恶性循环。这些发现共同提供了反应性小胶质细胞与AMD发病机理中异常补体蛋白相互作用的证据。但是，仅探索两个系统的基本机制。在这个后续项目中，我们假设通过受体介导的募集和激活，特别是过敏毒素补体裂解产物C3A和C5A维持慢性小胶质细胞反应性。我们进一步假设，过度反射灶可能会反映补体调节的小胶质细胞反应，因此可以用于监测AMD患者和动物模型中的疾病发育。该项目被细分为四个特定目标，在这些目标中，我们将确定C3A/C5A过敏毒素在体外对小胶质细胞的影响，测试小胶质细胞C3A/C5A受体缺乏在激光-CNV中的影响和光损伤模型，并评估人类维持式元素的表达和本地化，并最终与C3AR/C5AR的本地化有关。在AMD患者和对照组中。这些研究的结果将为AMD的免疫相关病因提供新的见解，并可能促进新的有效治疗的发展。