Restoration of homeostatic microglia in CNS inflammation

中枢神经系统炎症中小胶质细胞稳态的恢复

• 批准号: 10426253
• 负责人: Oleg Butovsky
• 金额: $ 37.5万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426253
• 关键词: Ablation; Address; Apolipoprotein E; Brain; CD14 gene; Cells; Central Nervous System Diseases; Chronic; Data; Demyelinations; Development; Disease; Disease Progression; Epigenetic Process; Experimental Autoimmune Encephalomyelitis; FCGR3B gene; Functional disorder; Genetic; Genetic Transcription; Immune; Infiltration; Inflammation; Inflammatory; Innate Immune Response; Interferon Type II; Interferons; Maps; Mediating; Microglia; Molecular; Molecular Profiling; Multiple Sclerosis; Mus; Myelogenous; Myeloid Cells; Nerve Degeneration; Nervous System Physiology; Neuraxis; Neurologic; Neutrophil Infiltration; Paralysed; Pathway interactions; Peripheral; Phenotype; Predisposition; Prevention; Publishing; Recovery; Regulation; Relapse; Research; Resolution; Role; Secondary Progressive Multiple Sclerosis; Signal Transduction; Systems Biology; T-Lymphocyte; Transforming Growth Factor beta; base; cell motility; chronic inflammatory disease; combinatorial; effective therapy; macrophage; monocyte; motor disorder; mouse model; multiple sclerosis patient; neurodegenerative phenotype; novel; novel therapeutic intervention; prevent; programs; recruit; restoration; success; tool; transcription factor

PROJECT SUMMARY Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by focal T cell and myeloid cell infiltrates leading to demyelination and loss of neurologic function. Activated microglia and macrophages are the predominant inflammatory cells in active or chronic MS plaques, and they persist in secondary-progressive MS. Despite advances in our understanding of MS pathophysiology, there are minimal disease-modifying treatments or preventions for innate-mediated, secondary-progressive forms of MS. We recently found that mutually antagonistic pathways driven by TGFβ and APOE signaling in microglia, dictate a phenotypic switch between homeostatic (M0) and neurodegenerative (MGnD) phenotypes. Using a systems biology approach, we identified major transcriptional and epigenetic regulators of M0- and MGnD- microglia. Finally, we reveal a new role for TGFβ-IFNγ signaling in the reprogramming of peripheral monocytes into microglia-like cells with the M0-molecular signature. Based on our published and preliminary data, we hypothesize that modulating the APOE-TGFβ/IFNγ pathway will restore the homeostatic-tolerogenic microglia and ameliorate EAE. We will address our hypothesis in the following aims: Aim 1: Replenish M0-homeostatic microglia via APOE-TGFβ/IFNγ signaling in EAE In this Aim, we will determine 1) the impact of TGFβ/IFNγ signaling on the replenishment of M0-microglia in EAE; 2) the regulatory networks controlled by APOE-TGFβ signaling underlying microglia phenotype regulation in EAE; and 3) fate-map analysis of microglia phenotype switch during peak and recovery stage of EAE. Aim 2: Reprogram monocytes into MG-like cells via APOE-TGFβ/IFNγ pathway in EAE and from MS patients In this Aim, we will determine 1) whether targeting Apoe in Ly6CHi monocytes facilitates the acquisition of the M0-microglial transcriptional program; 2) the molecular mechanisms underlying TGFβ/IFN-mediated reprogramming of Ly6CHi monocytes; and 3) whether modulation of the APOE-TGFβ/IFN pathway in CD14+/CD16– monocytes isolated from MS subjects induces the M0-microglial transcriptional program to serve as a novel therapeutic approach for progressive MS. Successful completion will result in: 1) identification of molecular mechanisms mediated by APOE-TGFβ/IFNγ signaling in microglia and monocyte phenotype regulation that contribute to the development, progression and resolution of EAE, and 2) understanding the role of APOE-TGFβ/IFNγ signaling in reprogramming of peripheral monocytes into homeostatic microglia-like cells in EAE and from MS patients.

项目摘要 多发性硬化症（MS）是中枢神经系统（CNS）的慢性炎症性疾病 通过局灶性T细胞和髓样细胞浸润，导致神经功能的脱髓鞘和丧失。活性 小胶质细胞和巨噬细胞是活性或慢性MS斑块中的主要炎症细胞，它们是 坚持二级制作MS。尽管我们对MS病理生理学的理解有所进步，但仍有 MS先天介导的次要促进形式的最小疾病改良治疗或预防措施。 我们最近发现，由TGFβ和APOE信号传导驱动的相互拮抗途径，小胶质细胞， 决定稳态（M0）和神经退行性（MGND）表型之间的表型切换。使用 系统生物学方法，我们确定了M0和MGND-的主要转录和表观遗传调节剂 小胶质细胞。最后，我们揭示了TGFβ-IFNγ信号传导在周围单核细胞重编程中的新作用 带有M0分子特征的小胶质细胞样细胞。根据我们已发布和初步数据，我们 假设调节APOE-TGFβ/IFNγ途径将恢复稳态抗胆碱性小胶质细胞 和改善EAE。我们将在以下目的中解决我们的假设： AIM 1：通过EAE中的APOE-TGFβ/IFNγ信号补充M0整体小胶质细胞 在此目的中，我们将确定1）TGFβ/IFNγ信号传导对补充M0-微神经的影响 伊2）由APOE-TGFβ信号传导控制的小胶质细胞表型调节的调节网络 在伊3）在EAE的峰值和恢复阶段，小胶质细胞表型转换的命运图分析。 AIM 2：通过APOE-TGFβ/IFNγ途径在EAE和MS中重新编程单核细胞进入MG样细胞 患者 在此目标中，我们将确定1）针对LY6CHI单核细胞中的APOE是否有助于获取 M0-Microglial转录程序； 2）TGFβ/IFN介导的分子机制 重编程Ly6chi单核细胞； 3）是否调制APOE-TGFβ/IFN途径中的途径是否调制 从MS受试者中分离出的CD14+/CD16 - 单核细胞会影响M0-Microglial转录程序以服务 作为渐进式MS的新型热方法。 成功完成将导致：1）鉴定由APOE-TGFβ/IFNγ介导的分子机制 小胶质细胞和单核细胞表型调节的信号传导，有助于发展，进展和 EAE的分辨率和2）了解APOE-TGFβ/IFNγ信号在重新编程中的作用 EAE和MS患者的单核细胞进入稳态小胶质细胞样细胞。