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：
10228062
负责人：
Michael Alex Wheeler
金额：
$ 9.45万
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 2022-07-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10228062
关键词：
Animal Model Astrocytes Autoimmune Responses Binding Proteins Blood - brain barrier anatomy Cells Cellular Stress 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 Neuraxis Neurodegenerative Disorders Neuroglia Neurologic Deficit Neurons Pathogenesis Pathogenicity Pathway interactions Pharmacology Phase Play Population Proteins Refractory Regulation Research Personnel Role Sampling Signal Pathway Signal Transduction T-Lymphocyte Techniques Therapeutic Therapeutic Intervention Transcriptional Activation Tumor-infiltrating immune cells Work base clinically relevant cost disability efficacious treatment inhibitor/antagonist monocyte mouse model multiple sclerosis patient nervous system disorder neurotoxic new therapeutic target novel programs receptor receptor expression recruit response single-cell RNA sequencing small molecule targeted treatment therapeutic evaluation therapeutic target therapy development transcription factor transcriptomics 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）是中枢神经系统（CNS）的一种慢性炎症性神经退行性疾病，是年轻人残疾的主要原因，遭受约40万美国公民的影响，每年产生约100亿美元的经济负担。 MS是由于遗传因素与环境因素之间的相互作用不完全理解的，这会触发针对CNS髓磷脂的自身免疫反应。慢性CNS炎症会在CNS居民细胞（如星形胶质细胞和小胶质细胞）中诱导促炎性程序，这些细胞对当前可用于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，它们参与健康和疾病中CNS稳态的多个方面，包括MS及其动物模型，实验性自身免疫性脑脊髓炎（EAE）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能会确定MS中疾病发病机理的机制以及新型的有效疗法，特别是在其渐进阶段。在以前关注MS环境因素的研究中，我们确定了由环境污染物控制的星形胶质细胞中的信号传导途径，并驱动了促进EAE和MS中炎症和神经变性的星形胶质细胞致病活性。具体而言，我们发现内质网（ER）置换受体Sigmar1稳定了需要酶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，从而促进了促进促炎基因在促炎的基因中的表达。在遗传扰动研究中，我们证明了SIGMAR1驱动的IRE1A-XBP1激活可以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，IL6，IL6，IL6，CSF2（GM-CSF）（GM-CSF），以及CSF2RA（CSF2RA）（CSF2RA）（csf2ra（CSF2RA）（gm-CSF受体）。此外，我们检测到局限于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）。通过单单细胞RNA测序（SCRNA-SEQ）在EAE（AIM 1.1）和MS（AIM 1.1）和MS（AIM 1.1）和MS（AIM 1.1）中，由SIGMAR1-IRE1A-XBP1信号传导（XBP1+星形胶质细胞）驱动的星形胶质细胞亚群。目标2：指导阶段（K99）。使用EAE小鼠模型（AIMS 2.1-2.2）和SCRNA-SEQ（AIM 2.3），用临床相关的SIGMAR1抑制剂抑制XBP1信号传导的治疗潜力。 AIM 3：独立研究者阶段（R00）。研究使用包括壁ice-seq（AIM 3.1）和Merfish（AIM 3.2）的空间转录组方法来研究XBP1+星形胶质细胞中GM-CSF信号传导的调节。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，确定控制它的分子机制，并评估其药理操作的治疗价值。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells.

乳酸通过稳定树突状细胞中的 HIF-1α 来限制 CNS 自身免疫。

DOI：
10.1038/s41586-023-06409-6
发表时间：
2023
期刊：
Nature
影响因子：
64.8
作者：
Sanmarco,LilianaM;Rone,JosephM;Polonio,CarolinaM;FernandezLahore,Gonzalo;Giovannoni,Federico;Ferrara,Kylynne;Gutierrez-Vazquez,Cristina;Li,Ning;Sokolovska,Anna;Plasencia,Agustin;FaustAkl,Camilo;Nanda,Payal;Heck,EvelinS;Li,
通讯作者：
Li,

Protocol for inducing inflammation and acute myelin degeneration in larval zebrafish.