Molecular Mechanisms of IL-17-dependent autoimmune signaling

IL-17依赖性自身免疫信号传导的分子机制

• 批准号: 9913154
• 负责人: Sarah L Gaffen
• 金额: $ 51.42万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-05 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913154
• 关键词: Address; Antibodies; Attention; Autoimmune Process; Autoimmunity; Binding; Biological; Biological Markers; Biological Models; Biological Response Modifiers; Blocking Antibodies; Bone Marrow; CCAAT-Enhancer-Binding Proteins; CCAAT-enhancer-binding protein-delta; Cell Cycle Kinetics; Cells; Chimera organism; Data; Development; Diabetes Mellitus; Diagnostic; Disease; Drug Targeting; Epithelial; Epithelium; Equilibrium; Evaluation; Event; Exhibits; Experimental Autoimmune Encephalomyelitis; Foundations; Gene Expression; Genes; Genetic Transcription; Genetic Translation; Glomerulonephritis; Goals; Immune response; Immune system; Impairment; Infection; Inflammation; Inflammatory; Interleukin-17; Interleukin-6; Interleukins; LCN2 gene; Lead; Link; Lymphocyte; Mediating; Mediator of activation protein; Mesenchymal; Messenger RNA; Modeling; Molecular; Multiple Sclerosis; Mus; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Process; Protein Family; Proteins; Psoriasis; RNA-Binding Proteins; Refractory; Regulation; Resistance; Risk; Role; Signal Transduction; Signaling Molecule; System; T-Lymphocyte; Therapeutic; Thermogenesis; Tissues; Transcript; Translations; cell type; clinical efficacy; immunopathology; in vivo; interest; mRNA Expression; mRNA Stability; member; microorganism; novel; pathogen; pre-clinical; receptor; therapeutic target; transcription factor; γδ T cells

IL-17 and Th17 cells drive pathology in a variety of autoimmune and pathologic inflammatory conditions. Recently, biologic drugs targeting the IL-17 pathway have shown clinical efficacy in psoriasis, and are under evaluation for other autoimmune and inflammatory disease conditions. We have a long-standing interest in understanding the fundamental basis for IL-17 signaling, with the premise that defining the molecular mediators of disease pathology will ultimately help lead to development of the most effective or specific therapeutic targets, diagnostics or biomarkers. IL-17 regulates downstream inflammatory genes by transcriptional mechanisms, mainly involving the canonical NF-κB pathway as well as CCAAT/Enhancer binding proteins (C/EBPs). IL-17 also activates numerous post-transcriptional mechanisms that control mRNA stability and translation. In a screen to identify new intermediates involved in IL-17-dependent downstream signaling, we discovered that IL-17 induces a novel RNA binding protein (RBP) that was never previously linked to IL-17 signaling, T cells or autoimmune pathology. Strikingly, cells lacking this RBP exhibited markedly impaired in IL-17 signaling, especially activation of NF-κB and C/EBPδ. In vivo, mice lacking this RBP were refractory to IL-17-driven inflammatory diseases, including experimental autoimmune encephalomyelitis (EAE), a model of MS, and AGN, a model of autoimmune glomerulonephritis. The goals of this application are to define the mechanisms by which this novel RBP pathway controls IL-17-dependent signal transduction (Aim 1) and the tissue-specific consequences to IL-17-induced autoimmune pathology using EAE as a model system (Aim 2).

IL-17和Th17细胞在多种自身免疫性和病理性疾病中的作用 炎症状态。最近，针对IL-17途径的生物药物已经 已显示出对银屑病的临床疗效，并正在评估其他自身免疫性和 炎症性疾病状况。我们长期以来一直有兴趣了解 IL-17信号的基本基础，前提是定义分子 疾病病理的介体最终将有助于大多数 有效或特定的治疗靶点、诊断或生物标志物。IL-17调节 下游的炎症基因通过转录机制，主要涉及 典型的NF-κB途径以及CCAAT/增强子结合蛋白(C/EBPs)。IL-17 也激活了许多控制mRNA稳定性的转录后机制 还有翻译。在屏幕上识别参与IL-17依赖的新中间体 在下游信号传递过程中，我们发现IL-17诱导了一种新的RNA结合蛋白 (RBP)以前从未与IL-17信号、T细胞或自身免疫有关 病理学。值得注意的是，缺乏这种RBP的细胞在IL-17中表现出明显的损伤 信号转导，尤其是核因子-κB和C/EBPδ的激活。在体内，缺乏这种RBP的小鼠 对IL-17驱动的炎症性疾病无效，包括实验性 自身免疫性脑脊髓炎(EAE)是MS的模型，AGN是MS的模型 自身免疫性肾炎。此应用程序的目标是定义 这一新的RBP途径控制IL-17依赖信号的机制 转导(AIM 1)与IL-17诱导的自身免疫的组织特异性后果 以EAE为模型系统的病理学(目标2)。