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

基本信息

批准号：
10619113
负责人：
Michael Alex Wheeler
金额：
$ 24.9万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10619113
关键词：
Animal Model Astrocytes Autoimmune Responses Binding Proteins Blood - brain barrier anatomy Cells Cellular Stress Central Nervous System Central Nervous System Diseases Chronic Data Development Disease Disease model Economic Burden Endoplasmic Reticulum Environmental Pollutants Environmental Risk Factor Enzymes Experimental Autoimmune Encephalomyelitis Experimental Models Factor X Gene Expression Genetic Genetic Transcription Goals Granulocyte-Macrophage Colony-Stimulating Factor Granulocyte-Macrophage Colony-Stimulating Factor Receptors Health Herbicides Homeostasis Human Inflammation Inflammatory Inositol Lesion Link Mediating Mentors Metabolic Control Microglia Molecular Multiple Sclerosis Multiple Sclerosis Lesions Mus Myelin Natural Immunity Nerve Degeneration Nervous System Physiology Neurodegenerative Disorders Neuroglia Neurologic Deficit Neurons Pathogenesis Pathogenicity Pathway interactions Peptide Initiation Factors Phase Play Population Proteins Refractory Regulation Research Personnel Role Sampling Signal Pathway Signal Transduction T-Cell Activation T-Lymphocyte Techniques Therapeutic Therapeutic Intervention Transcriptional Activation Work clinically relevant cost disability efficacious treatment immune cell infiltrate inhibitor monocyte mouse model multiple sclerosis patient nervous system disorder neurotoxic new therapeutic target novel pharmacologic programs receptor receptor expression recruit response single-cell RNA sequencing small molecule synergism targeted treatment therapeutic evaluation therapeutic target therapy development transcription factor transcriptomics translational potential young adult

项目摘要

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.

多发性硬化症 (MS) 是一种中枢神经系统 (CNS) 的慢性炎症性神经退行性疾病，是导致年轻人残疾的主要原因，困扰着约 40 万美国公民，每年造成约 100 亿美元的经济负担。 MS 是由于遗传因素和环境因素之间的相互作用尚不完全清楚而导致的，这种相互作用会引发针对中枢神经系统髓磷脂的自身免疫反应。慢性中枢神经系统炎症会在星形胶质细胞和小胶质细胞等中枢神经系统驻留细胞中诱导促炎症程序，这些细胞对目前可用于多发性硬化症的治疗方法没有反应。星形胶质细胞是丰富的中枢神经系统驻留细胞，参与健康和疾病中中枢神经系统稳态的多个方面，包括多发性硬化症及其动物模型、实验性自身免疫性脑脊髓炎（EAE）背景下的促炎信号传导。因此，对调节星形胶质细胞促炎活性的机制的研究可以确定多发性硬化症的疾病发病机制，以及新的有效疗法，特别是针对其进展阶段。在之前针对多发性硬化症环境因素的研究中，我们发现星形胶质细胞中的一条信号通路受环境污染物控制，并驱动星形胶质细胞致病活动，从而促进 EAE 和多发性硬化症中的炎症和神经变性。具体来说，我们发现内质网 (ER) 定位受体 SigmaR1 可以稳定肌醇需要酶 1-α (IRE1a)，从而激活转录因子 X-box 结合蛋白 1 (XBP1)，从而促进促炎基因星形胶质细胞中的表达。在遗传扰动研究中，我们证明 SigmaR1 驱动的 IRE1a-XBP1 激活可增强星形胶质细胞中促炎和神经毒性转录程序的表达，例如 Nos2、Ccl2、Il6、Csf2 (GM-CSF) 和 Csf2ra（GM-CSF 受体））在 EAE 期间。此外，我们检测到多发性硬化症病变部位的星形胶质细胞中 IRE1a-XBP1 激活增加。我假设 SigmaR1-IRE1a-XBP1 信号传导驱动 EAE 和 MS 中星形胶质细胞的致病活动。因此，我提出以下目标：目标 1：指导阶段 (K99)。使用单细胞 RNA 测序 (scRNA-seq) 定义 EAE (目标 1.1) 和 MS (目标 1.2) 中由 SigmaR1-IRE1a-XBP1 信号驱动的星形胶质细胞亚群 (XBP1+ 星形胶质细胞)。目标 2：指导阶段 (K99)。使用 EAE 小鼠模型（目标 2.1-2.2）和 scRNA-seq（目标 2.3）测试临床相关 SigmaR1 抑制剂抑制 XBP1 信号传导的治疗潜力。目标 3：独立调查员阶段 (R00)。使用空间转录组学方法（包括 NICHE-seq（目标 3.1）和 MERFISH（目标 3.2））研究 XBP1+ 星形胶质细胞中 GM-CSF 信号传导的调节。总而言之，这些研究将定义一种新的与疾病相关的星形胶质细胞群，确定控制它的分子机制，并评估其药理操作的治疗价值。