Control of Local CNS Inflammation

控制局部中枢神经系统炎症

• 批准号: 10241956
• 负责人: Francisco J. Quintana
• 金额: $ 35.84万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241956
• 关键词: Agonist; Aryl Hydrocarbon Receptor; Astrocytes; Autoimmune; Biological Response Modifiers; CD4 Positive T Lymphocytes; CISH gene; CNS autoimmune disease; CNS autoimmunity; Cells; Central Nervous System Diseases; Chronic; Clinical; Data; Dendritic Cells; Development; Disease; Drug Delivery Systems; Experimental Autoimmune Encephalomyelitis; Genes; Genetic Transcription; Genomics; Goals; Heterogeneity; In Vitro; Inflammation; Inflammatory; Ligands; Link; Mediating; Modeling; Mucous Membrane; Multiple Sclerosis; Neuraxis; Neurologic; Nose; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Peripheral; Phase; Play; Population; Pre-Clinical Model; Receptor Activation; Receptor Signaling; Regulation; Role; Route; Signal Transduction; System; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Transactivation; Transcriptional Regulation; Tryptophan; Work; base; defined contribution; dietary; disability; efficacious treatment; gut microbiota; inhibitor/antagonist; interdisciplinary approach; interest; multiple sclerosis patient; nano-string; nervous system disorder; neurotoxic; neurotoxicity; novel; novel therapeutics; programs; receptor expression; response; single-cell RNA sequencing; targeted treatment; therapeutic target; tool; transcription factor; young adult

PROJECT SUMMARY Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that constitutes the leading cause of neurologic disability in young adults. Astrocytes play important roles in MS and its model, experimental autoimmune encephalomyelitis (EAE), but the regulation of astrocyte activity is poorly understood. The study of astrocyte regulation is likely to identify mechanisms of pathogenesis and therapeutic targets in MS, particularly for its secondary progressive phase for which no efficacious therapies are available. We identified a pathway controlled by the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) that regulates astrocyte function during inflammation. Briefly, AhR in astrocytes promotes the expression of Suppressor Of Cytokine Signaling 2 (SOCS2), an inhibitor of NF-κB activation. AhR deletion in astrocytes up-regulates NF-κB activation and worsens EAE. These data suggest that AhR/SOCS2 signaling suppresses astrocyte pathogenic activities in EAE by limiting NF-κB activation. In support of this interpretation, nasal administration of the AhR agonist ITE suppresses EAE through a mechanism mediated by AhR in astrocytes. Moreover, agonists derived from dietary tryptophan (Trp) and the gut flora ameliorate EAE via AhR in astrocytes. These AhR agonists are decreased in MS patients, suggesting that deficient AhR activation contributes to disease pathogenesis. Collectively, these findings identify a novel AhR/SOCS2 pathway that integrates endogenous and environmental signals to control astrocyte function. We hypothesize that AhR in astrocytes limits CNS inflammation and is a potential therapeutic target for MS. Our specific aims are: SPECIFIC AIM 1: DOES AHR SUPPRESS ASTROCYTE-DRIVEN NEUROTOXICITY DURING EAE? We propose to: 1) Determine the effects of AhR in astrocytes on neurotoxicity during EAE, 2) Establish the effects of SOCS2 on NF-κB activation and astrocyte neurotoxicity, 3) Determine whether AhR limits NF-κB- driven astrocyte neurotoxicity via SOCS2. SPECIFIC AIM 2: HOW DOES AHR CONTROL THE TRANSCRIPTIONAL PROGRAM OF ASTROCYTES? We propose to: 1) Determine the role of AhR in the control of the transcriptional response of astrocytes during EAE, 2) Define the contribution of SOCS2 to the transcriptional effects of AhR in astrocytes, 3) Establish the heterogeneity of astrocyte responses and their control by AhR during EAE by single cell RNA-Seq. SPECIFIC AIM 3: IS AHR A THERAPEUTIC TARGET TO MODULATE ASTROCYTE FUNCTION? We propose to: 1) Evaluate the effects on astrocytes and CNS inflammation of AhR activation by ITE administered nasally, 2) Define the role of AhR/SOCS2 in astrocytes on the chronic progressive NOD EAE, which models important aspects of SPMS, 3) Evaluate the therapeutic value of nasal ITE in NOD EAE. IN SUMMARY, this project uses unique experimental systems to study the role of a novel AhR/SOCS2 pathway in astrocytes on CNS inflammation and its potential as a therapeutic target.

项目摘要 多发性硬化症（MS）是中枢神经系统（CNS）的自身免疫性疾病， 是年轻人神经系统残疾的主要原因。星形胶质细胞在MS及其模型中起重要作用， 实验性自身免疫性脑脊髓炎（EAE），但星形胶质细胞活性的调节较差 明白对星形胶质细胞调节的研究有可能确定发病机制和治疗机制 多发性硬化症的目标，特别是对于没有有效疗法的第二进展期。 我们确定了一个由配体激活的转录因子芳烃受体控制的途径 (AhR)在炎症过程中调节星形胶质细胞的功能。简言之，星形胶质细胞中的AhR促进了 细胞因子信号转导抑制因子2（SOCS 2），一种NF-κB活化抑制剂。星形胶质细胞中的AhR缺失 上调NF-κB活化并抑制EAE。这些数据表明AhR/SOCS 2信号转导抑制了 星形胶质细胞通过限制NF-κB活化在EAE中的致病活性。为了支持这一解释，鼻 施用AhR激动剂ITE通过星形胶质细胞中AhR介导的机制抑制EAE。 此外，来源于饮食色氨酸（Trp）和肠道植物群的激动剂通过AhR改善EAE， 星形胶质细胞这些AhR激动剂在MS患者中减少，表明AhR激活缺陷 有助于疾病的发病机制。总的来说，这些发现确定了一种新的AhR/SOCS 2途径， 整合内源性和环境信号以控制星形胶质细胞功能。我们假设AhR在 星形胶质细胞限制CNS炎症，是MS的潜在治疗靶点。我们的具体目标是： 特定目的1：AHR是否抑制EAE期间星形胶质细胞驱动的神经毒性？ 我们的目的是：1）确定星形胶质细胞中AhR在EAE神经毒性中的作用，2）建立 SOCS 2对NF-κB活化和星形胶质细胞神经毒性的影响，3）确定AhR是否限制NF-κB- 通过SOCS 2驱动星形胶质细胞神经毒性。 具体目标2：AHR如何控制星形胶质细胞的移行性增殖？ 我们提出：1）确定AhR在控制星形胶质细胞转录反应中的作用， EAE，2）确定SOCS 2对星形胶质细胞中AhR转录作用的贡献，3）建立 通过单细胞RNA-Seq在EAE期间星形胶质细胞反应异质性及其由AhR控制 特定目的3：AHR是调节星形胶质细胞功能的治疗靶点吗？ 本研究拟：1）评价ITE激活AhR对星形胶质细胞和中枢神经系统炎症的影响 2）确定AhR/SOCS 2在星形胶质细胞中对慢性进行性NOD EAE的作用， 3）评价鼻ITE对NOD EAE的治疗价值。 总之，该项目使用独特的实验系统来研究新型AhR/SOCS 2的作用。 星形胶质细胞中的信号通路对中枢神经系统炎症的影响及其作为治疗靶点的潜力。