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：
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
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/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

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 细胞驱动多种自身免疫和病理学的病理学最近，针对IL-17途径的生物药物已出现。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我们长期以来对了解炎症性疾病有着浓厚的兴趣。 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)。还激活许多控制 mRNA 稳定性的转录后机制和翻译，以确定涉及 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引人注目的是，缺乏这种 RBP 的细胞 IL-17 显着受损。缺乏这种 RBP 的小鼠体内，尤其是 NF-κB 和 C/EBPδ 的激活。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）本申请的目标是定义自身免疫性肾小球肾炎。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）。