Desialylation as trigger of microglia responses in the aging and degenerating retina

去唾液酸化作为衰老和退化视网膜中小胶质细胞反应的触发因素

• 批准号: 500260917
• 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: Priority Programmes
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/500260917?language=en
• 关键词: Desialylation; trigger; microglia; responses; aging; Desialylation; trigger; microglia; responses; aging

Age-dependent retinal degeneration are major causes for vision loss and blindness. A chronic pro-inflammatory environment often orchestrated by microglia is a hallmark of these diseases. Reactive oxygen species (ROS) and complement components (C1q, C3) produced and released by microglia and macrophages have been postulated to contribute to the progression of retinal degeneration. Sialylation is a major checkpoint for the control of the complement system and microglial responses. The amount of sialylation significantly reduces with aging in humans, but its relevance for complement- and microglia-associated disease including age-related macular degeneration (AMD) is unclear. In this project we will study the effect of reduced sialylation on the microglial state in the retina of Gne+/- mice and compare this phenotype to the aging and degenerating human retina in the context of AMD. Gne+/- mice will be crossed with Cx3cr1-GFP reporter animals and mice will be challenged with acute white light exposure. Non-invasive spectral domain optical coherence tomography (SD-OCT) and confocal scanning laser ophthalmoscopy (SLO) will then be used for a controlled temporal analysis of photoreceptor demise and microglia responses in the retina. In addition, we will analyze the sialylation state, microglial phenotype and RNAseq-based transcriptome of human post-mortem retinal tissue derived from AMD patients and aged controls. Combining these in vivo analyses of mice with retinal in situ immunohistochemistry and RNAseq analysis of mice and humans will enable us to define the critical time points when a slight loss of sialylation alerts microglia and triggers retinal degeneration. These experiments can aid to elucidate the relevance of desialylation as trigger of microglia responses in mice and humans during aging and may highlight this biochemical pathway as potential therapy target for age-related retinal diseases.

依赖年龄的视网膜变性是视力丧失和失明的主要原因。这些疾病的标志是经常由小胶质细胞策划的慢性促炎环境。已经假定，由小胶质细胞和巨噬细胞产生和释放的活性氧（ROS）和补体成分（C1Q，C3）已被认为有助于视网膜变性的进展。 SiAlylation是控制补体系统和小胶质响应的主​​要检查点。人类溶解的量显着降低，但与补体和小胶质细胞相关疾病在内的相关性（包括与年龄相关的黄斑变性（AMD））尚不清楚。在这个项目中，我们将研究溶解度降低对gne +/-小鼠视网膜小胶质细胞状态的影响，并将这种表型与AMD背景下的衰老和退化的人类视网膜进行比较。 gne +/-小鼠将与CX3CR1-GFP记者动物交叉，小鼠将受到急性白光暴露的挑战。非侵入性光谱结构域光学相干断层扫描（SD-OCT）和共聚焦扫描激光眼镜检查（SLO）将用于视网膜中光感受器衰老和小胶质细胞反应的受控时间分析。此外，我们还将分析源自AMD患者和老年对照组的人验尸后的小胶质表型和基于RNASEQ的转录组。将这些小鼠的体内分析与视网膜原位免疫组织化学和小鼠和人类的RNASEQ分析相结合，将使我们能够定义关键时间点，而siallylation略有损失会警告小胶质细胞和触发视网膜变性。这些实验可以有助于阐明脱酰化作为小鼠和人类在衰老过程中的小胶质细胞反应的相关性，并可能突出这种生化途径作为与年龄相关的视网膜疾病的潜在治疗靶标。