Molecular Control of Astrocytes in CNS Inflammation

中枢神经系统炎症中星形胶质细胞的分子控制

• 批准号: 10817084
• 负责人: Michael Alex Wheeler
• 金额: $ 3.97万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10817084
• 关键词: Animal Model; Astrocytes; Autoimmune Responses; Binding Proteins; Cells; Central Nervous System; Central Nervous System Diseases; Chronic; Disease; Disease model; Economic Burden; Endoplasmic Reticulum; Environmental Pollutants; Environmental Risk Factor; Enzymes; Experimental Autoimmune Encephalomyelitis; Factor X; Gene Expression; Genetic; Genetic Transcription; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor Receptors; Health; Homeostasis; Inflammation; Inflammatory; Inositol; Mentors; Microglia; Molecular; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myelin; Nerve Degeneration; Neurodegenerative Disorders; Pathogenesis; Pathogenicity; Pathway interactions; Phase; Population; Regulation; Research Personnel; Role; Sampling; Signal Pathway; Signal Transduction; Techniques; Therapeutic; Transcriptional Activation; clinically relevant; disability; efficacious treatment; inhibitor; mouse model; multiple sclerosis patient; neurotoxic; new therapeutic target; novel; pharmacologic; programs; receptor; single-cell RNA sequencing; therapeutic evaluation; transcriptomics; young adult

PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disorder of the central nervous system (CNS) and is the leading cause of disability in young adults, afflicting some 400,000 U.S. citizens and generating an economic burden of approximately $10 billion annually. MS results from an incompletely understood interaction between genetic and environmental factors that triggers an autoimmune response against CNS myelin. Chronic CNS inflammation induces pro-inflammatory programs in CNS-resident cells such as astrocytes and microglia, which are not responsive to the therapeutic approaches currently available for MS. Astrocytes are abundant CNS-resident cells which participate in multiple aspects of CNS homeostasis in health and disease, including pro-inflammatory signaling in the context of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Thus, the study of the mechanisms that regulate astrocyte pro-inflammatory activities may identify mechanisms of disease pathogenesis in MS, as well as novel efficacious therapies, particularly for its progressive phase. In previous studies focused on environmental factors in MS, we identified a signaling pathway in astrocytes that is controlled by environmental pollutants, and drives astrocyte pathogenic activities that promote inflammation and neurodegeneration in EAE and MS. Specifically, we found that the endoplasmic reticulum (ER)-localized receptor SigmaR1 stabilizes the inositol requiring enzyme 1-alpha (IRE1a), leading to the activation of the transcription factor X-box binding protein 1 (XBP1) which promotes pro-inflammatory gene expression in astrocytes. In genetic perturbation studies we demonstrated that SigmaR1-driven IRE1a-XBP1 activation boosts the expression of pro-inflammatory and neurotoxic transcriptional programs in astrocytes such as Nos2, Ccl2, Il6, Csf2 (GM-CSF), and Csf2ra (the GM-CSF receptor) during EAE. Moreover, we detected increased IRE1a-XBP1 activation in astrocytes localized to MS lesions. I hypothesize that SigmaR1-IRE1a- XBP1 signaling drives astrocyte pathogenic activities in EAE and MS. Thus, I propose the following Aims: AIM 1: Mentored phase (K99). Define astrocyte subpopulations driven by SigmaR1-IRE1a-XBP1 signaling (XBP1+ astrocytes) in both EAE (Aim 1.1) and MS (Aim 1.2) using single-cell RNA sequencing (scRNA-seq). AIM 2: Mentored phase (K99). Test the therapeutic potential of suppressing XBP1 signaling with clinically- relevant SigmaR1 inhibitors using EAE mouse models (Aims 2.1-2.2), and scRNA-seq (Aim 2.3). AIM 3: Independent investigator phase (R00). Study the regulation of GM-CSF signaling in XBP1+ astrocytes using spatial transcriptomic approaches including NICHE-seq (Aim 3.1) and MERFISH (Aim 3.2). Taken together, these studies will define a novel disease-associated astrocyte population, identify the molecular mechanisms that control it, and evaluate the therapeutic value of its pharmacologic manipulation.

项目摘要/摘要 多发性硬化症（MS）是中枢神经系统的慢性炎症性神经退行性疾病 （CNS），是年轻人残疾的主要原因，折磨了约40万美国公民并产生 每年的经济负担约为100亿美元。 MS来自未知的结果 遗传因素与环境因素之间的相互作用，这些因素触发了针对CNS的自身免疫反应 髓线。慢性CNS炎症诱导CNS居民细胞（例如星形胶质细胞）的促炎程序 和小胶质细胞，它们对当前可用于MS的治疗方法没有反应。星形胶质细胞是 大量的CNS居民细胞参与了CNS稳态在健康和疾病中的多个方面， 在MS及其动物模型的背景下，包括促炎性信号传导，实验自身免疫 脑脊髓炎（EAE）。因此，研究调节星形胶质细胞促炎活性的机制 可能确定MS中疾病发病机理的机制以及新型的有效疗法，特别是针对 它的渐进阶段。在以前关注MS环境因素的研究中，我们确定了信号传导 由环境污染物控制的星形胶质细胞中的途径，并驱动星形胶质细胞致病活动 这促进了EAE和MS中的炎症和神经退行性。具体来说，我们发现内质 网状（ER）集量受体Sigmar1稳定需要酶1-α（IRE1A）的肌醇，导致导致 转录因子X-box结合蛋白1（XBP1）的激活，该蛋白1（XBP1）促进促炎基因 星形胶质细胞的表达。在遗传扰动研究中，我们证明了SIGMAR1驱动的IRE1A-XBP1 激活增强了星形胶质细胞中促炎和神经毒性转录程序的表达 在EAE期间，如NOS2，CCL2，IL6，CSF2（GM-CSF）和CSF2RA（GM-CSF受体）。而且，我们发现 在局限于MS病变的星形胶质细胞中的IRE1A-XBP1激活增加。我假设sigmar1-ire1a- XBP1信号传导驱动EAE和MS中的星形胶质细胞致病活性。因此，我提出以下目的： 目标1：指导阶段（K99）。定义由Sigmar1-ire1a-XBP1信号驱动的星形胶质细胞亚群 （XBP1+星形胶质细胞）在EAE（AI​​M 1.1）和MS（AIM 1.2）中都使用单细胞RNA测序（SCRNA-SEQ）。 目标2：指导阶段（K99）。测试使用临床上抑制XBP1信号传导的治疗潜力 使用EAE小鼠模型（AIMS 2.1-2.2）和SCRNA-SEQ（AIM 2.3）的相关SIGMAR1抑制剂。 AIM 3：独立研究者阶段（R00）。研究XBP1+星形胶质细胞中GM-CSF信号的调节 使用包括壁ice-seq（AIM 3.1）和Merfish（AIM 3.2）的空间转录组方法。 综上所述，这些研究将定义与疾病相关的星形胶质细胞种群 控制它并评估其药理操作的治疗价值的机制。