RNA binding proteins in end-organ autoimmune pathology

终末器官自身免疫病理学中的 RNA 结合蛋白

基本信息

批准号：
10450945
负责人：
Partha Sarathi Biswas
金额：
$ 63.32万
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：
2022
资助国家：
美国
起止时间：
2022-02-08 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10450945
关键词：
Anti-Glomerular Basement Membrane Disease Antibodies Antigen Targeting Antineutrophil Cytoplasmic Antibodies Autoantibodies Autoimmune Autoimmune Diseases Autoimmunity Automobile Driving Binding Biological Biological Markers Biological Response Modifiers Biopsy CCAAT-Enhancer-Binding Proteins CCAAT-enhancer-binding protein-delta Cells Complex Cytokine Signaling Data Deposition Disease Drug Targeting Elements Epithelial Cells Equilibrium Event Gene Expression Generations Genes Genetic Transcription Glomerulonephritis Goals Goodpasture Syndrome Half-Life Helper-Inducer T-Lymphocyte Human Image Immune system Immunology Impairment Inflammation Interleukin-17 Interleukin-6 Kidney Kidney Diseases LCN2 gene Lead Mediating Messenger RNA Modification Molecular Molecular Target Mus Neutrophil Infiltration Organ Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Physiological Post-Transcriptional Regulation Process Production Publishing RNA RNA-Binding Proteins Regulation Resistance Role Signal Transduction Tissues Translations Tubular formation Up-Regulation Vasculitis autoinflammation autoinflammatory base cell type chemokine cytokine improved in vivo kidney biopsy kidney cell kidney vascular structure microorganism mouse model murine antibody novel pathogen renal damage success targeted treatment transcription factor

项目摘要

IL-17 and Th17 cells are dysregulated in many pathologic auto-inflammatory conditions. Antibody-mediated glomerulonephritis (AGN) occurs when unchecked inflammation triggered by autoimmune Ab complexes that deposit in glomeruli and lead to kidney damage, which occurs in conditions such as Goodpasture disease, ANCA vasculitis, etc. Although the initiators of autoantibody-mediated pathology differ, the terminal events in end organ kidney damage have many common hallmarks, and the fundamental immunology of this process is still not well understood. Accumulating evidence from our groups and others have convincingly demonstrated role for IL-17 in driving pathogenesis of AGN in humans and in mouse models. Excessive autoimmune pathology can be caused by hyper-production of cytokines from T helper cells or by over-exuberant cytokine signaling. Therefore, in principle, molecules that influence IL-17 signal transduction have the potential to be viable targets for therapy in settings where this cytokine is a disease driver. In probing the fundamental mechanisms that mediate IL-17-dependent signaling, we identified two novel RNA binding proteins (RBPs) that contribute significantly to the pathogenesis of AGN in vivo. These RBPs are downstream of IL-17 and their activities in the IL- 17 pathway are interconnected through regulation of CCAAT Enhancer Binding Protein (C/EBP) transcription factors. In turn, C/EBPs mediate IL-17-dependent effectors that promote renal inflammation, including Lipocalin-2, neutrophil-recruiting chemokines, and feed-forward activators of Th17 differentiation such as IL-6. Our central hypothesis is that IL-17 promotes inflammation through post-transcriptional regulation of downstream mRNAs that drive renal pathology in AGN. This proposal will evaluate the molecular mechanisms by which these RBPs act and the specific physiological functions in the setting of AGN.

在许多病理自动炎症条件下，IL-17和TH17细胞失调。当未检查的炎症触发时，发生抗体介导的肾小球肾炎（AGN）自身免疫性AB复合物沉积在肾小球中并导致肾脏损伤，发生在诸如Goodpasture疾病，ANCA血管炎等的疾病。尽管自身抗体介导的病理学不同，最终器官肾脏损伤中的末端事件具有许多常见的标志，以及此过程的基本免疫学仍然不好理解。我们团体和其他人的积累证据令人信服地证明 IL-17在人类和小鼠模型中驱动AGN发病机理中的作用。过多的自身免疫性病理可能是由T辅助细胞的细胞因子过度生产或过度溶出的细胞因子信号传导。因此，原则上，影响IL-17信号的分子转导有可能成为在这种细胞因子为一个的环境下进行治疗的可行靶标疾病驱动器。在探测介导IL-17依赖性信号传导的基本机制时，我们确定了两个新型的RNA结合蛋白（RBP），它们对 AGN体内的发病机理。这些RBP位于IL-17的下游及其在IL-的活动 17途径通过调节CCAAT增强子结合蛋白（C/EBP）互连转录因子。反过来，C/EBP介导促进肾脏的IL-17依赖性效应子炎症，包括Lipocalin-2，中性粒细胞促进趋化因子和前馈激活剂 Th17差异化（例如IL-6）。我们的中心假设是IL-17促进炎症通过对驱动AGN肾脏病理的下游mRNA的转录后调节。该建议将评估这些RBP的分子机制和特定的分子机制 AGN环境中的生理功能。