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：
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
项目类别：
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

项目摘要

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.

项目概要/摘要多发性硬化症 (MS) 是一种中枢神经系统慢性炎症性神经退行性疾病 (CNS)，是导致年轻人残疾的主要原因，困扰着约 40 万美国公民，并产生了每年约100亿美元的经济负担。 MS 结果源于不完全理解遗传和环境因素之间的相互作用引发针对中枢神经系统的自身免疫反应髓磷脂。慢性中枢神经系统炎症会诱导星形胶质细胞等中枢神经系统驻留细胞的促炎程序和小胶质细胞，它们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、实验性自身免疫背景下的促炎症信号传导脑脊髓炎（EAE）。因此，对星形胶质细胞促炎活性调节机制的研究可以确定多发性硬化症的发病机制，以及新的有效疗法，特别是对于它的进步阶段。在之前针对 MS 环境因素的研究中，我们发现了一个信号传导星形胶质细胞中受环境污染物控制并驱动星形胶质细胞致病活动的途径促进 EAE 和 MS 的炎症和神经变性。具体来说，我们发现内质网状 (ER) 定位受体 SigmaR1 稳定需要酶 1-α (IRE1a) 的肌醇，从而导致转录因子 X-box 结合蛋白 1 (XBP1) 的激活可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 激活促进星形胶质细胞中促炎和神经毒性转录程序的表达，例如 EAE 期间的 Nos2、Ccl2、Il6、Csf2 (GM-CSF) 和 Csf2ra（GM-CSF 受体）。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)。定义由 SigmaR1-IRE1a-XBP1 信号驱动的星形胶质细胞亚群使用单细胞 RNA 测序 (scRNA-seq) 在 EAE (目标 1.1) 和 MS (目标 1.2) 中检测 (XBP1+ 星形胶质细胞)。目标 2：指导阶段 (K99)。通过临床试验测试抑制 XBP1 信号传导的治疗潜力使用 EAE 小鼠模型（目标 2.1-2.2）和 scRNA-seq（目标 2.3）研究相关 SigmaR1 抑制剂。目标 3：独立调查员阶段 (R00)。研究 XBP1+ 星形胶质细胞中 GM-CSF 信号传导的调节使用空间转录组学方法，包括 NICHE-seq（目标 3.1）和 MERFISH（目标 3.2）。总而言之，这些研究将定义一个新的与疾病相关的星形胶质细胞群，识别分子控制它的机制，并评估其药理学操作的治疗价值。