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（MS）是中枢神经系统（CNS）的炎性脱髓鞘疾病。 越来越多的证据表明，髓鞘再生的抑制是永久性脑缺血的主要原因。 神经变性然而，抑制OPCs分化和髓鞘再生的确切机制 仍然是一个活跃的研究领域。虽然炎症相关的NOTCH 1激活与 MS中髓鞘再生缺陷，NOTCH 1参与炎症过程的确切机制， 反应仍然难以捉摸。使用实验性自身免疫性脑脊髓炎（EAE），MS的动物模型， 我们和其他人已经确定IL-17信号传导对于CNS中炎症的诱导是至关重要的。我们 我现在发现了IL-17和NOTCH 1信号的直接整合， OPCs的分化。IL-17刺激诱导NOTCH 1细胞内结构域（NICD 1）的释放 在与星形胶质细胞共培养的OPC中。从机制上讲，IL-17 R通过细胞外基质与NOTCH 1相互作用。 结构域，其促进NICD 1的切割。随后，ACT 1（IL-17信号传导的衔接蛋白）， 与NICD 1形成复合物，随后Act 1-NICD 1复合物易位到细胞核中。Act1-NICD 1 复合物促进含有转录复合物的RBP-J在NOTCH 1启动子上的组装 CNS炎症相关的靶基因。此外，诱饵肽破坏IL-17 RA-NOTCH 1 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IL-17诱导的NICD裂解。 EAE模型髓鞘脱失。基于这些发现，我们假设IL-17-NOTCH 1通路驱动了 表达一组特定的基因以促进炎症和抑制OPC分化，从而 损害脱髓鞘疾病中的髓鞘再生过程。我们将通过目标1来检验这一假设： 研究IL-17-NOTCH 1整合抑制OPC分化的分子机制。 目的2：研究IL-17-NOTCH 1整合对髓鞘再生过程的影响。完成 这一提议将为IL-17信号通路的关键整合提供基本的见解， NOTCH 1是脱髓鞘疾病发病机制的基础，为脱髓鞘疾病提供了新的治疗策略。 促进髓鞘再生。