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: 10349504
• 负责人: Anne Schaefer
• 金额: $ 39.83万
• 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/10349504
• 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 associated microglia; 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; Testing; Tissues; Toxic effect; Transcriptional Regulation; attenuation; gene function; genomic locus; in vivo; inhibitor; macrophage; neuronal survival; neuroprotection; neurotoxic; neurotoxicity; novel; novel therapeutic intervention; 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 我们的建议着重于小胶质细胞介导的大脑体内平衡调节的表观遗传机制 和神经脱生。我们最近的研究揭示了大脑区域特异性小胶质细胞的规范和 建议该规范与功能不同的大脑区域中不同的神经元表型匹配。我们 结果表明，区域小胶质细胞规范取决于polycomb抑制复合物2（PRC2）， 哪些以特定于大脑区域的方式使小胶质细胞基因沉默。 PRC2“放松”规格的消融 小胶质细胞，然后是神经退行性的神经元功能和行为的变化。这些发现 提出一个模型，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 导致小胶质介导的神经元损伤的因素的异常产生。为了检验我们的假设， 我们建议确定不同大脑区域中小胶质细胞中的PRC2靶标，并确定 PRC2在区域小胶质细胞规范上失活。 PRC2已显示在下游 不同的信号通路包括RAF/ERK信号通路，已与 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触发 控制小胶质细胞增殖，吞噬和/或促炎的基因的异常表达 通过直接影响PRC2功能的活动。我们将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。 神经退行性期间的许多小胶质细胞介导的毒性涉及炎症的激活 回答。我们的建议旨在识别支持该基因调节机制 小胶质细胞的促炎活性。我们发现将组蛋白乙酰化和 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。我们表明，对BET的药物抑制会导致小胶质细胞的选择性抑制 体外和体内炎症基因表达。 BET家族包括结构上不同的BRD2， BRD3和BRD4蛋白，所有这些蛋白在小胶质细胞中均表达。我们以前观察到差异 单个BET蛋白与巨噬细胞和神经元中不同基因靶靶标的结合。与小鼠一起使用 有条件的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。总之， 拟议的研究将确定区域特异性小胶质细胞规范的新型表观遗传机制 这些机制对神经变性的贡献。识别控制不同的蛋白质 小胶质细胞活性状态将促进预防新型治疗方法的发展 和/或神经变性的衰减。