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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：
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
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/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

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细胞驱动各种自身免疫和病理病理