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

基本信息

批准号：
10524055
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
项目类别：
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/10524055
关键词：
Address Antibodies Attention Autoimmune Autoimmune Diseases Autoimmunity Binding Biological Biological Markers Biological Models Biological Response Modifiers Blocking Antibodies Bone Marrow CCAAT-Enhancer-Binding Proteins Cell Cycle Kinetics Cells Chimera organism Data Development Diabetes Mellitus Diagnostic Disease Drug Targeting Epithelium Equilibrium Evaluation Event Exhibits Experimental Autoimmune Encephalomyelitis Foundations Gene Expression Genes Genetic Transcription Glomerulonephritis Goals IL17 gene Immune response Immune system Impairment Infection Inflammation Inflammatory Interleukin-6 Interleukins LCN2 gene Lead Link Lymphocyte Mediating Mediator Mesenchymal Messenger RNA Modeling Molecular Multiple Sclerosis Mus Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Process Production Protein Family Proteins Psoriasis RNA-Binding Proteins Refractory Regulation Resistance Risk Role Signal Induction Signal Transduction Signal Transduction Induction Signaling Molecule System T-Lymphocyte Therapeutic Thermogenesis Tissues Transcript Translations cell type clinical efficacy immunopathology in vivo interest mRNA Expression mRNA Stability mRNA Translation member microorganism novel pathogen posttranscriptional pre-clinical receptor therapeutic target transcription factor γδ T cells

项目摘要

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和病理学中驱动病理炎症条件。最近，针对IL-17途径的生物药具有显示牛皮癣的临床效率，并且正在评估其他自身免疫性和炎症性疾病状况。我们对理解 IL-17信号传导的基本基础，并以定义分子的前提疾病病理学介体最终将有助于发展最大的发展有效或特定的治疗靶标，诊断或生物标志物。 IL-17调节通过转录机制下游炎症基因，主要涉及规范NF-κB途径以及CCAAT/增强子结合蛋白（C/EBP）。 IL-17 还激活了控制mRNA稳定性的众多转录后机制和翻译。在屏幕中识别涉及IL-17依赖性的新中间体下游信号传导，我们发现IL-17影响了新型RNA结合蛋白（RBP）以前从未与IL-17信号传导，T细胞或自身免疫接触病理。令人惊讶的是，缺乏这种RBP暴露的细胞在IL-17中显着受损信号传导，尤其是NF-κB和C/EBPδ的激活。在体内，小鼠缺乏这种RBP 对IL-17驱动的炎症性疾病难治性，包括实验性疾病自身免疫性脑脊髓炎（EAE），一种MS模型和AGN，一种模型自身免疫性肾小球肾炎。该应用的目标是定义这种新型RBP途径控制IL-17依赖性信号的机制转导（AIM 1）和针对IL-17诱导的自身免疫的组织特异性后果使用EAE作为模型系统的病理学（AIM 2）。