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

• 批准号: 10569112
• 负责人: Partha Sarathi Biswas
• 金额: $ 64.36万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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/10569112
• 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; Blood Vessels; 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; Glomerulonephritis; Goals; Goodpasture Syndrome; Half-Life; Helper-Inducer T-Lymphocyte; Human; IL17 gene; Image; Immune system; Immunology; Impairment; Inflammation; Interleukin-6; Kidney; Kidney Diseases; LCN2 gene; Mediating; Messenger RNA; Modification; Molecular; Molecular Target; Mus; Neutrophil Infiltration; Organ; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Physiological; Post-Transcriptional Regulation; Process; Publishing; RNA; RNA-Binding Proteins; Regulation; Resistance; Role; Signal Transduction; Tissues; Translations; Tubular formation; Up-Regulation; Vasculitis; autoinflammation; autoinflammatory; cell type; chemokine; cytokine; improved; in vivo; kidney biopsy; kidney cell; microorganism; mouse model; murine antibody; novel; pathogen; posttranscriptional; renal damage; success; targeted treatment; transcription factor

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.

IL-17和Th17细胞在许多病理性自身炎性病症中失调。 抗体介导的肾小球肾炎（AGN）发生时，未经检查的炎症触发的 自身免疫抗体复合物，存款在肾小球中并导致肾损伤，发生在 条件，如古德帕斯彻病，ANCA血管炎等。 自身抗体介导的病理学不同，终末器官肾损伤的终末事件有 许多共同的标志，这一过程的基本免疫学仍然不是很好 明白从我们的团队和其他人那里积累的证据已经令人信服地证明了 IL-17在人类和小鼠模型中驱动AGN发病机制中的作用。过度 自身免疫病理学可由T辅助细胞过度产生细胞因子或由 过度旺盛的细胞因子信号传导。因此，原则上，影响IL-17信号的分子 转导有可能成为治疗的可行靶点，在这种细胞因子是一种细胞因子的环境中， 疾病司机在探索介导IL-17依赖性信号传导的基本机制时， 我们发现了两种新的RNA结合蛋白（RBP），它们对细胞凋亡有重要作用。 AGN在体内的发病机制。这些RBP是IL-17的下游，并且它们在IL-17中的活性在IL-17中是不稳定的。 17条途径通过调节CCAAT增强子结合蛋白（C/EBP）相互关联 转录因子反过来，C/EBP介导IL-17依赖性效应物，其促进肾功能。 炎症，包括Lipocalin-2、趋化因子和前馈激活剂 Th17分化，如IL-6。我们的中心假设是IL-17促进炎症 通过下游mRNA的转录后调节，驱动AGN中的肾脏病理。 该提案将评估这些RBP作用的分子机制和特定的 活动星系核的生理功能。