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

小胶质细胞炎症状态的年龄依赖性激活及其表观遗传调节

• 批准号: 10032850
• 负责人: Anne Schaefer
• 金额: $ 299.43万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10032850
• 关键词: Ablation; Acute; Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animals; Attenuated; BRD2 gene; Binding; Brain; Brain region; Bromodomain; Cells; Chromatin; Communicable Diseases; Data; Development; Disease; Disease Progression; Enhancers; Epigenetic Process; Exposure to; Foundations; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Human; Immune; Immunity; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Influenza; Lead; Life; Link; Mediating; Microglia; Modeling; Monitor; Mus; Natural Immunity; Nature; Nerve Degeneration; Neurodegenerative Disorders; Onset of illness; Output; Pharmacology; Phenotype; Physiological; Play; Poly I-C; Process; Production; Proteins; Recording of previous events; Risk Factors; Role; Severity of illness; Signal Transduction; Stimulus; Testing; Therapeutic; Tissues; Training; Transcriptional Regulation; Up-Regulation; age related; aging brain; cell type; cytokine; genomic locus; immune activation; imprint; in vivo; inhibitor/antagonist; macrophage; neuroinflammation; neurotoxic; novel strategies; novel therapeutic intervention; prevent; response

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.

项目摘要 该提案涉及衰老过程中系统性小胶质细胞激活的表观遗传机制及其 对神经退行性疾病的贡献。小鼠和人类的衰老与 促炎基因在小胶质细胞中的表达和小胶质细胞促炎激活被认为是一种 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。年龄相关 小胶质细胞驱动的炎症的增加与小胶质细胞对炎症的异常升高的反应有关。 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 训练免疫力，其中初始免疫细胞暴露于各种促炎原因定量， 细胞对环境触发的反应中的质的持久变化。我们假设 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， 动物或人的生命。我们认为，传染病，其中许多可以发生在生命的早期， 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。 暴露于促炎触发因素会留下一个表观遗传印记，从而导致炎症加剧 衰老小胶质细胞中的基因表达。为了验证这一假设，我们将诱导短暂的全身炎症， 小鼠，然后分析不同年龄的基因表达。基因的长期变化 先天性免疫细胞激活后的表达先前已与潜伏性免疫细胞的激活有关。 增强剂。我们建议在初始激活后确定小胶质细胞增强子的激活状态， 通过终身监测增强子活性。我们证明了用 BET蛋白质的药理学抑制剂，在增强子活性中起重要作用，导致有效的 在体外和体内抑制小胶质细胞活化。最值得注意的是，用BET抑制剂治疗具有主要的 对患有AD的小鼠的治疗效果。我们将讨论个人BET的具体贡献 促炎基因表达和增强子激活的蛋白质， 神经变性这一信息与我们对表观遗传机制的理解高度相关， 控制全身与年龄相关的小胶质细胞炎症状态，并可能导致新的 用于治疗神经变性疾病的方法。