Age-dependent activation of microglia inflammatory state and its epigenetic modulation

项目摘要 这一建议解决了衰老过程中系统性小胶质细胞激活的表观遗传学机制及其 对神经退行性疾病的贡献。小鼠和人类的衰老与增加的 小胶质细胞中促炎基因的表达和促炎活性被认为是其中之一 包括阿尔茨海默病在内的与年龄相关的神经退行性疾病的原因。与年龄相关的 小胶质细胞驱动的炎症增加与小胶质细胞对 不同的炎症刺激。衰老过程中小胶质细胞激活的增强状态类似于 训练有素的免疫力，最初免疫细胞对各种促炎因素的暴露可以量化和 细胞对环境诱因的反应发生了质的持久的变化。我们假设增加了 小胶质细胞的促炎活性反映了小胶质细胞暴露于炎症信号的历史 动物或人类的生命。我们认为，传染病，其中许多可能发生在生命的早期，以及 伴随的全身性炎症使小胶质细胞暴露于外周来源的促炎信号。 暴露在促炎因素下可能会留下表观遗传印记，从而推动炎症加剧 衰老小胶质细胞的基因表达。为了验证这一假设，我们将在 然后分析不同年龄组小鼠的基因表达。基因的长期变化 先天免疫细胞激活后的表达以前与潜伏期的激活有关 增强剂。我们建议在最初激活之后确定小胶质细胞增强剂的激活状态 通过对增强剂活性的终生监测。我们证明了小胶质细胞的治疗 BET蛋白的药理抑制剂在增强活性方面起着突出的作用，导致了 体外和体内抑制小胶质细胞激活。最值得注意的是，使用BET抑制剂治疗有一个主要的 对阿尔茨海默病小鼠的治疗作用。我们将讨论个人投注的具体贡献 在衰老和衰老过程中促进促炎基因表达和增强因子激活的蛋白质 神经退行性变。这一信息与我们对表观遗传机制的理解高度相关 控制全身性年龄相关的小胶质细胞炎症状态，并可能导致新的 神经退行性疾病的治疗方法。

Project Summary This proposal addresses the epigenetic mechanisms of systemic microglia activation during ageing and its contribution to neurodegenerative diseases. Ageing in mice and human is associated with the increased expression of pro-inflammatory genes in microglia and microglia pro-inflammatory activation is considered one of the causes of age-associated neurodegenerative diseases including Alzheimer disease. The age-associated increase in microglia-driven inflammation is linked to an aberrantly heightened response of microglia to different inflammatory stimuli. The enhanced state of microglia activation during ageing resembles the state of trained immunity where initial immune cell exposure to various pro-inflammatory causes quantitate and qualitative long-lasting changes in cell responses to environmental triggers. We hypothesize that increased pro-inflammatory activity of microglia reflects the history of microglia exposure to inflammatory signals during animal or human life. We argue that infectious diseases, many of which can occur early in life, and the accompanied systemic inflammation exposes microglia to periphery-derived pro-inflammatory signals. Exposure to pro-inflammatory triggers can leave an epigenetic imprint that drives heightened inflammatory gene expression in ageing microglia. To test this hypothesis, we will induce transient systemic inflammation in mice followed by the analysis of gene expression at differed ages. The long-lasting changes in gene expression that follow innate immune cell activation has been previously linked to the activation of latent enhancers. We propose to determine the activation state of microglia enhancers after initial activation followed by the lifelong monitoring of the enhancer activity. We demonstrated that treatment of microglia with pharmacological inhibitors of BET proteins, that play a prominent role in enhancer activity, leads to the potent suppression of microglia activation in vitro and in vivo. Most notably, treatment with BET inhibitors has a major therapeutic impact on mice that suffer from AD. We will address the specific contribution of individual BET proteins to pro-inflammatory gene expression and enhancer activation during ageing and in neurodegeneration. This information is highly relevant for our understanding of the epigenetic mechanisms that govern the systemic age-associated microglial inflammatory state and may lead to the development of novel approaches for the treatment of neurodegenerative diseases.