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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要多发性硬化症 (MS) 是一种中枢神经系统 (CNS) 炎症性脱髓鞘疾病。越来越多的证据表明，髓鞘再生的抑制是永久性髓鞘再生的主要原因。然而，抑制OPCs分化和髓鞘再生的精确机制。仍然是一个活跃的研究领域，而炎症相关的 NOTCH1 激活也与此有关。 MS 中的髓鞘再生缺陷，NOTCH1 在炎症过程中参与的精确机制使用实验性自身免疫性脑脊髓炎（EAE）（一种多发性硬化症动物模型）的反应仍然难以捉摸。我们和其他人已经确定 IL-17 信号传导对于中枢神经系统炎症的诱导至关重要。现在发现 IL-17 和 NOTCH1 信号传导的直接整合在损伤中起主导作用 IL-17刺激诱导NOTCH1（NICD1）胞内结构域的释放。在与星形胶质细胞共培养的 OPC 中，IL-17R 通过细胞外与 NOTCH1 相互作用。结构域，促进 NICD1 的裂解，随后，Act1（IL-17 信号转导的接头蛋白）与 NICD1 形成复合物，然后 Act1-NICD1 复合物易位到细胞核中。复合物促进含有 RBP-J 的转录复合物在 NOTCH1 启动子上的组装与中枢神经系统炎症有关的靶基因此外，诱饵肽会破坏 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 增殖并减弱基于这些发现，我们追踪了 IL-17-NOTCH1 通路驱动 EAE 模型中的髓鞘质丢失的情况。表达一组特定基因以促进炎症并抑制 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 检验这一假设：探讨IL-17-NOTCH1整合对OPC分化抑制作用的分子机制。目标 2：研究 IL-17-NOTCH1 整合对髓鞘再生过程完成的体内影响。该提案将为 IL-17 和 IL-17 信号通路的关键整合提供基本见解 NOTCH1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通过促进多发性硬化症患者的髓鞘再生。