Transcriptional control of microglia diversification and inflammation

小胶质细胞多样化和炎症的转录控制

• 批准号: 9973836
• 负责人: Anne Schaefer
• 金额: $ 41.47万
• 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: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9973836
• 关键词: Ablation; Address; Affect; Animal Model; Area; Automobile Driving; BRAF gene; BRD2 gene; Behavior; Binding; Brain; Brain region; Bromodomain; Cells; Cognition; Complex; DNA Polymerase II; Data; Development; Disease; Epigenetic Process; Family; Family member; Foundations; Gene Expression; Gene Expression Profile; Gene Silencing; Gene Targeting; Genes; Genetic Transcription; Histone Acetylation; Homeostasis; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Link; Mediating; Mediator of activation protein; Microglia; Modeling; Mus; Myeloid Cells; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathologic; Pathway interactions; Phagocytosis; Pharmacology; Phenotype; Plant Roots; Play; Polycomb; Prevention approach; Production; Protein Family; Protein Inhibition; Proteins; RNA; Regulation; Regulator Genes; Research; Role; Signal Pathway; Signal Transduction; Structure; Testing; Tissues; Toxic effect; Transcriptional Regulation; attenuation; gene function; genomic locus; in vivo; inhibitor/antagonist; macrophage; neuronal survival; neuroprotection; neurotoxic; neurotoxicity; novel; novel therapeutic intervention; novel therapeutics; response; synaptic function

Project Summary Our proposal focuses on the epigenetic mechanisms of microglia-mediated regulation of brain homeostasis and neuro-degeneration. Our recent studies revealed brain region-specific microglia specification and suggested that this specification matches distinct neuron phenotypes in functionally distinct brain areas. We showed that regional microglia specification depends on the Polycomb Repressive Complex 2 (PRC2), which silences microglia genes in a brain-region specific fashion. Ablation of PRC2 “relaxes” specification of microglia followed by neurodegenerative-like changes in neuronal function and behavior. These findings suggest a model where interaction between “matching” neurons and microglia renders microglia from the aberrant production of factors responsible for microglial-mediated neuronal damage. To test our hypothesis, we propose to identify PRC2 targets in microglia in different brain regions and to determine the impact of PRC2 inactivation on regional microglia specification. PRC2 has been shown to operate downstream of different signaling pathways including the RAF/Erk signaling pathway, which has been implicated in microglia-mediated neurotoxicity. We hypothesize that activation of these signaling pathways may trigger the aberrant expression of genes controlling microglia proliferation, phagocytosis and/or proinflammatory activity by directly affecting PRC2 function. We will address the link between signal-induced microglia-driven neurotoxicity and PRC2-mediated gene silencing. Much of the microglia-mediated toxicity during neurodegeneration involves the activation of inflammatory responses. Our proposal aims at identification of the gene regulatory mechanisms supporting the proinflammatory activity of microglia. We found that BET proteins, which link histone acetylation and activation of RNA Pol II, play a key role in the signal-induced transcription of proinflammatory genes in microglia. We show that the pharmacological inhibition of BET leads to the selective suppression of microglia inflammatory gene expression in vitro and in vivo. The BET family includes the structurally different BRD2, BRD3 and BRD4 proteins, all of which are expressed in microglia. We previously observed differential binding of individual BET proteins to distinct gene targets in macrophages and neurons. Using mice with conditional microglia-specific inactivation, we will determine the contribution of individual BET proteins to brain region-specific microglia phenotypes in the healthy brain and during neurodegeneration. In summary, the proposed research will identify novel epigenetic mechanisms of region-specific microglia specification and the contribution of these mechanisms to neurodegeneration. Identification of proteins controlling distinct states of microglia activity will facilitate the development of novel therapeutic approaches for the prevention and/or attenuation of neurodegeneration.

项目概要 我们的提案重点关注小胶质细胞介导的大脑稳态调节的表观遗传机制 我们最近的研究揭示了大脑区域特异性的小胶质细胞规范和 表明该规范与功能不同的大脑区域中不同的神经表型相匹配。 表明区域小胶质细胞规范取决于多梳抑制复合物 2 (PRC2)， 它以大脑区域特定的方式沉默小胶质细胞基因，消除 PRC2“放松”规范。 这些发现导致小胶质细胞的神经功能和行为发生类似神经退行性的变化。 提出了一个模型，其中“匹配”神经元和小胶质细胞之间的相互作用使小胶质细胞从 导致小胶质细胞介导的神经元损伤的因子的异常产生为了检验我们的假设。 我们建议确定不同大脑区域小胶质细胞中的 PRC2 靶标，并确定 PRC2 对区域小胶质细胞规范的失活已被证明在下游起作用。 不同的信号通路，包括 RAF/Erk 信号通路，该通路与 我们认为这些信号通路的激活可能会触发小胶质细胞介导的神经毒性。 控制小胶质细胞增殖、吞噬作用和/或促炎症的基因的异常表达 我们将通过直接影响 PRC2 功能来解决信号诱导的小胶质细胞驱动之间的联系。 神经毒性和 PRC2 介导的基因沉默。 神经变性过程中小胶质细胞介导的大部分毒性涉及炎症的激活 我们的建议旨在确定支持的基因调控机制。 我们发现 BET 蛋白将组蛋白乙酰化与小胶质细胞的促炎活性联系起来。 RNA Pol II 的激活，在促炎基因的信号诱导转录中发挥关键作用 我们发现 BET 的药理抑制会导致小胶质细胞的选择性抑制。 BET 家族包括结构不同的 BRD2、 BRD3 和 BRD4 蛋白均在小胶质细胞中表达，我们之前观察到差异。 使用小鼠进行单个 BET 蛋白与巨噬细胞和神经元中不同基因靶标的结合。 条件性小胶质细胞特异性失活，我们将确定单个 BET 蛋白对小胶质细胞特异性失活的贡献 健康大脑和神经变性过程中大脑区域特异性的小胶质细胞表型。 拟议的研究将确定区域特异性小胶质细胞规范的新表观遗传机制 以及这些机制对神经变性的控制的贡献。 小胶质细胞的活动状态将有助于开发新的预防治疗方法 和/或神经变性的减弱。