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: 10304158
• 负责人: Sarah L Gaffen
• 金额: $ 50.69万
• 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/10304158
• 关键词: Address; Antibodies; Attention; Autoimmune; 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; 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 细胞驱动多种自身免疫和病理学的病理学 炎症状况。近年来，针对IL-17通路的生物药物已 显示出对牛皮癣的临床疗效，并且正在评估其他自身免疫性疾病和 炎症性疾病状况。我们长期以来一直有兴趣了解 IL-17 信号传导的基本基础，前提是定义了分子 疾病病理学的调节因素最终将有助于导致大多数疾病的发展 有效或特定的治疗靶点、诊断或生物标志物。 IL-17 调节 通过转录机制调节下游炎症基因，主要涉及 典型的 NF-κB 通路以及 CCAAT/增强子结合蛋白 (C/EBP)。白细胞介素17 还激活许多控制 mRNA 稳定性的转录后机制 和翻译。筛选涉及 IL-17 依赖性的新中间体 下游信号传导，我们发现 IL-17 诱导一种新型 RNA 结合蛋白 (RBP) 以前从未与 IL-17 信号传导、T 细胞或自身免疫相关 病理。引人注目的是，缺乏这种 RBP 的细胞在 IL-17 方面表现出明显受损 信号传导，特别是 NF-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（包括实验性炎症）具有难治性 自身免疫性脑脊髓炎 (EAE)（MS 模型）和 AGN（MS 模型） 自身免疫性肾小球肾炎。该应用程序的目标是定义 这种新型 RBP 通路控制 IL-17 依赖性信号的机制 转导（目标 1）以及 IL-17 诱导的自身免疫的组织特异性后果 使用 EAE 作为模型系统进行病理学（目标 2）。