Regulation of IL-17 signaling by RNA binding proteins in kidney diseases

RNA 结合蛋白在肾脏疾病中调节 IL-17 信号传导

• 批准号: 9762270
• 负责人: Partha Sarathi Biswas
• 金额: $ 19.24万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762270
• 关键词: ARID Domain; Accounting; Antibodies; Antibody Therapy; Antipsychotic Agents; Apoptosis; Autoimmune Diseases; Autoimmune Process; Automobile Driving; Biology; Cells; Chlorpromazine; Chronic; Chronic Kidney Failure; Clinical; Cytokine Signaling; Data; Development; Disease; Epithelial Cells; Event; Gene Proteins; Glomerular basement membrane antibody; Glomerulonephritis; Goals; Grant; Human; IL17 Signaling Pathway; Immunosuppressive Agents; Inflammation; Inflammation Mediators; Inflammatory; Injury; Interleukin-17; Intervention; Kidney; Kidney Diseases; Kidney Failure; Knowledge; LCN2 gene; Lead; Lung; Lupus Nephritis; Mediating; Messenger RNA; Modeling; Molecular; Morbidity - disease rate; Mus; Organ; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Positioning Attribute; Post-Transcriptional Regulation; Pre-Clinical Model; Property; Proteins; Proteinuria; RNA-Binding Proteins; Receptor Signaling; Regulation; Renal function; Reporting; Role; Scheme; Signal Transduction; Therapeutic; Therapeutic immunosuppression; Tight Junctions; Tissues; Transcriptional Regulation; Tubular formation; Work; autoinflammatory; cell type; comparative; cytokine; effective therapy; efficacy testing; in vivo; inhibitor/antagonist; interest; kidney cell; kidney dysfunction; mortality; mouse model; new therapeutic target; podocyte; preclinical efficacy; prevent; renal damage; response; restraint; side effect; transcription factor

ABSTRACT Antibody-mediated glomerulonephritis (AGN) is a clinical manifestation of autoimmune kidney diseases. Strikingly, AGN is the second leading cause of kidney dysfunction in US, accounting for 20-30% of total renal failure cases. Response to immunosuppressive drugs is often inadequate and associated with significant side effects. Chronic inflammation in the glomerular and tubular compartments of the kidney lead to tissue damage, ultimately causing irreversible loss of renal function. Emerging data implicate the proinflammatory cytokine IL- 17 in the pathogenesis of AGN. The dominant focus in the IL-17 field has been on how IL-17-producing cells are generated, whereas comparatively little is known about regulation of downstream IL-17 signaling in relevant tissue cell types. Our new data show in a mouse model of AGN demonstrate IL-17 receptor signaling in non-hematopoietic cells is required for AGN pathogenesis. Hence, we will focus here on defining IL-17 signaling mechanisms and outcomes in specific renal cell types. Understanding this is important because tissue damage occurs locally, and interventions to limit such damage could be highly valuable clinically to treat the end-organ damage that characterizes AGN. Specifically, this proposal is centered around understanding the molecular basis of post-transcriptional control of mRNA in the context of two distinct kidney cell types, glomerular podocytes and rental tubule epithelial cells (RTECs). We recently identified two RNA binding proteins (RBPs), Regnase-1 and Arid5a, which act in an opposing manner to negatively and positively control IL-17 signaling, respectively. Of particular relevance to AGN, these RBPs control IL-17-dependent expression of Lipocalin-2, which exerts potent kidney-damaging properties. Our central hypothesis is that Regnase-1 restricts AGN development by limiting Lipocalin-2 expression in the nephritic kidney. In Aim 1, we will determine the impact of a selective Regnase-1 deficiency in kidney-resident podocytes and RTECs. Aim 2 will define signaling events involved in regulation of IL-17 signal transduction in mouse and human podocytes and RTECs. Additionally will evaluate the preclinical efficacy of treating mice with an Arid5a inhibitor in AGN, which we predict will allow increased restraint of IL-17 signaling through Regnase-1. These studies will advance our understanding of how pathogenic IL-17 signaling is regulated in the nephritic kidney to promote end-organ damage. Additionally, this work may reveal novel drug targets in the IL- 17 signaling pathway that can be exploited for treating IL-17-driven end-organ damage in other chronic kidney diseases involving this cytokine.

抽象的 抗体介导的肾小球肾炎（AGN）是自身免疫性肾脏疾病的临床表现。 令人惊讶的是，AGN是美国肾功能障碍的第二大主要原因，占肾脏总数的20-30％ 故障案件。对免疫抑制药物的反应通常不足，并且与明显的一面有关 效果。肾脏肾小球和管状室中的慢性炎症导致组织损伤， 最终导致不可逆转的肾功能丧失。新兴数据暗示促炎性细胞因子IL- 17在AGN的发病机理中。 IL-17领域的主要重点是如何产生IL-17的细胞 是生成的，而对于下游IL-17信号的调节，相对较少了解 相关的组织细胞类型。我们在AGN的鼠标模型中显示的新数据显示IL-17受体信号传导 AGN发病机理中需要非山摩托细胞。因此，我们将重点放在定义IL-17上 特定肾细胞类型中的信号传导机制和结果。理解这一点很重要，因为 组织损伤在当地发生，限制这种损害的干预措施在临床上可能非常有价值 特征AGN的最终器官损坏。具体而言，该提议集中在 在两个背景下了解mRNA转录后控制的分子基础 不同的肾细胞类型，肾小球足细胞和租赁小管上皮细胞（RTEC）。我们最近 确定了两个RNA结合蛋白（RBP），regnase-1和arid5a，它们以相反的方式起作用 分别负面控制IL-17信号传导。这些RBP与AGN特别相关 控制Lipocalin-2的IL-17依赖性表达，其发挥有效的肾脏损伤特性。我们的 中心假设是regnase-1通过限制Lipocalin-2在 肾肾。在AIM 1中，我们将确定选择性regnase-1缺乏症对肾脏居民的影响 足细胞和RTEC。 AIM 2将定义与调节IL-17信号转导调节有关的信号传导事件 小鼠和人类足细胞和RTEC。另外将评估治疗小鼠的临床前功效 使用AGN中的ARID5A抑制剂，我们预测，这将使IL-17信号的限制增加 regnase-1。这些研究将促进我们对病原IL-17信号如何调节如何调节的理解 肾肾脏肾脏可促进最终器官损伤。此外，这项工作可能揭示了IL-的新药物靶标 17可以利用用于治疗其他慢性肾脏IL-17驱动的最终器官损伤的信号通路 涉及这种细胞因子的疾病。