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.

项目摘要 我们的建议集中在小胶质细胞介导的调节脑内稳态的表观遗传机制 和神经退化我们最近的研究揭示了大脑区域特异性小胶质细胞的特化， 这表明，这种规格匹配不同的神经元表型在功能不同的大脑区域。我们 显示区域性小胶质细胞特化依赖于多梳抑制复合物2（PRC 2）， 以大脑特定区域的方式沉默小胶质细胞基因。PRC 2消融“松弛”规范 小胶质细胞随后神经元功能和行为的神经变性样变化。这些发现 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。为了验证我们的假设， 我们建议在不同的大脑区域的小胶质细胞中识别PRC 2靶点，并确定PRC 2靶点的影响。 PRC 2失活对局部小胶质细胞的影响。PRC 2已被证明是在 不同的信号传导途径，包括RAF/Erk信号传导途径，这与 小胶质细胞介导的神经毒性。我们假设这些信号通路的激活可能会触发 控制小胶质细胞增殖、吞噬作用和/或促炎作用的基因的异常表达 直接影响PRC 2的功能。我们将讨论信号诱导的小胶质细胞驱动的 神经毒性和PRC 2介导的基因沉默。 在神经变性过程中，许多小胶质细胞介导的毒性涉及炎症介质的激活。 应答我们的建议旨在确定基因调控机制，支持 小胶质细胞的促炎活性。我们发现，BET蛋白，连接组蛋白乙酰化和 RNA Pol II的激活，在信号诱导的促炎基因转录中起关键作用。 小胶质细胞我们发现，BET的药理学抑制导致小胶质细胞的选择性抑制， 在体外和体内炎症基因表达。BET家族包括结构上不同的BRD 2， BRD 3和BRD 4蛋白，它们都在小胶质细胞中表达。我们之前观察到 单个BET蛋白与巨噬细胞和神经元中的不同基因靶点的结合。使用小鼠， 条件性小胶质细胞特异性失活，我们将确定单个BET蛋白对 健康大脑和神经变性过程中的大脑区域特异性小胶质细胞表型。总的来说， 这项研究将确定区域特异性小胶质细胞特化的新表观遗传机制 以及这些机制对神经退行性变的作用。控制不同的蛋白质的鉴定 小胶质细胞活性的状态将促进新的治疗方法的发展， 和/或减弱神经变性。