THE INTEGRATION OF IL-17 AND NOTCH SIGNALING IN THE PATHOGENESIS OF CNS INFLAMMATION

IL-17 和 Notch 信号传导在中枢神经系统炎症发病机制中的整合

• 批准号: 10311763
• 负责人: Zizhen Kang
• 金额: $ 33.8万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311763
• 关键词: Ablation; Adaptor Signaling Protein; Address; Adult; Affect; Animal Model; Area; Astrocytes; Attenuated; Brain; Cell Differentiation process; Cell Nucleus; Cell Proliferation; Chronic; Complex; Cuprizone; Data; Demyelinating Diseases; Demyelinations; Disease model; Environment; Experimental Autoimmune Encephalomyelitis; Extracellular Domain; Genes; Genetic Transcription; IL17 Signaling Pathway; Impairment; Inflammation; Inflammatory; Inflammatory Response; Interleukin-17; Knock-in Mouse; Link; Mediating; Modeling; Molecular; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myelin; NOTCH1 gene; Nerve Degeneration; Neuraxis; Neurologic Deficit; Nuclear; Oligodendroglia; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peptides; Phase; Play; Process; Proliferating; Research; Role; Signal Transduction; Slice; Spinal Cord; Structure-Activity Relationship; Symptoms; Testing; Therapeutic; United States; Work; base; cell type; central nervous system demyelinating disorder; chromatin immunoprecipitation; cytokine; improved; in vivo; injury and repair; insight; multiple sclerosis patient; notch protein; novel therapeutic intervention; oligodendrocyte progenitor; programs; promoter; receptor; remyelination; six transmembrane epithelial antigen of the prostate 4; standard care; stem cell proliferation; stem cells; ubiquitin-protein ligase

Project Summary Multiple Sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). Increasing evidence indicates that the inhibition of remyelination is a major cause of the permanent neurodegeneration. However the precise mechanism that inhibits OPCs differentiation and remyelination remains an active area of research. While inflammation-associated NOTCH1 activation was implicated in defective remyelination in MS, the precise mechanism by which NOTCH1 was engaged during inflammatory response remains elusive. Using experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we and others have established that IL-17 signaling is crucial for the induction of inflammation in the CNS. We have now discovered a direct integration of IL-17 and NOTCH1 signaling that plays a dominant role in impairing the differentiation of OPCs. IL-17 stimulation induced the release of the intracellular domain of NOTCH1 (NICD1) in the OPCs co-cultured with astrocytes. Mechanistically, IL-17R interacts with NOTCH1 via the extracellular domain, which facilitates the cleavage of NICD1. Subsequently, Act1, the adaptor protein for IL-17 signaling, forms a complex with NICD1, followed by translocation of Act1-NICD1 complex into the nucleus. Act1-NICD1 complex promotes the assembly of RBP-J containing transcriptional complex on the promoters of NOTCH1 target genes implicated in CNS inflammation. Furthermore, a decoy peptide disrupting the IL-17RA–NOTCH1 interaction inhibited IL-17-induced NICD cleavage, reduced IL-17-induced OPC prolifereation and attenuated the myelin loss in EAE model. Based on these findings, we hypothesize IL-17-NOTCH1 pathway drives the expression of a specific set of genes to promote inflammation and inhibition of OPC differentiation, thereby impairing the remyelination process in the demyelinating disease. We will test this hypothesis through Aim 1: Investigate the molecular mechanism of the inhibitory role of IL-17-NOTCH1 integration on OPC differentiation. Aim 2: Investigate the in vivo impact of IL-17-NOTCH1 integration on remyelination process. The completion of this proposal will provide fundamental insight into the critical integration of signaling pathways of IL-17 and NOTCH1, which underlies the pathogenesis of demyelinating disease, offering novel therapeutic strategies for MS patients by promoting remyelination.

项目摘要 多发性硬化症（MS）是一种炎症性，脱髓鞘性疾病的中枢神经系统（CNS）。 越来越多的证据表明，抑制re髓是永久性的主要原因 神经变性。但是，抑制OPC分化和再髓的确切机制 仍然是研究的积极领域。虽然与炎症相关的Notch1激活涉及 MS中有缺陷的再髓，炎症过程中Notch1参与的精确机制 反应仍然难以捉摸。使用实验性自身免疫性脑脊髓炎（EAE），一种MS动物模型， 我们和其他人已经确定IL-17信号传导对于CNS诱导炎症至关重要。我们 现在已经发现了IL-17和Notch1信号的直接整合，在损害中起主要作用 OPC的区分。 IL-17刺激诱导Notch1的细胞内结构域的释放（NICD1） 在与星形胶质细胞共培养的OPC中。从机械上讲，IL-17R通过细胞外与Notch1相互作用 域，负责NICD1的裂解。随后，ACT1，用于IL-17信号传导的衔接蛋白， 与NICD1形成复合物，然后将ACT1-NICD1复合物转移到核中。 ACT1-NICD1 复合物促进了Notch1启动子上含有转录复合物的RBP-J的组装 CNS注射中实施的靶基因。此外，一种诱饵肽破坏了IL-17RA – NOTCH1 相互作用抑制IL-17诱导的NICD裂解，减少IL-17诱导的OPC增殖并减弱 EAE模型中的髓磷脂损失。根据这些发现，我们假设IL-17-Notch1途径驱动 表达一组特定基因以促进OPC分化的注射和抑​​制 损害脱髓鞘疾病中的再生过程。我们将通过目标1来检验这一假设： 研究IL-17-NOTCH1整合OPC分化的抑制作用的分子机制。 AIM 2：研究IL-17-Notch1整合对雷梅尔过程的体内影响。完成 该建议将为IL-17和 Notch1是脱髓鞘疾病的发病机理的基础，为新颖的治疗策略提供了 MS患者通过促进再髓式。