Regulation of IL-17 signaling by RNA binding proteins in kidney diseases
Regulation of IL-17 signaling by RNA binding proteins in kidney diseases
批准号:
9762270
负责人:
Partha Sarathi Biswas
金额:
$19.24万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-02-01 至 2021-01-31
关键词:
ARID DomainAccountingAntibodiesAntibody TherapyAntipsychotic AgentsApoptosisAutoimmune DiseasesAutoimmune ProcessAutomobile DrivingBiologyCellsChlorpromazineChronicChronic Kidney FailureClinicalCytokine SignalingDataDevelopmentDiseaseEpithelial CellsEventGene ProteinsGlomerular basement membrane antibodyGlomerulonephritisGoalsGrantHumanIL17 Signaling PathwayImmunosuppressive AgentsInflammationInflammation MediatorsInflammatoryInjuryInterleukin-17InterventionKidneyKidney DiseasesKidney FailureKnowledgeLCN2 geneLeadLungLupus NephritisMediatingMessenger RNAModelingMolecularMorbidity - disease rateMusOrganOutcomePathogenesisPathogenicityPathologicPathologyPatientsPharmaceutical PreparationsPositioning AttributePost-Transcriptional RegulationPre-Clinical ModelPropertyProteinsProteinuriaRNA-Binding ProteinsReceptor SignalingRegulationRenal functionReportingRoleSchemeSignal TransductionTherapeuticTherapeutic immunosuppressionTight JunctionsTissuesTranscriptional RegulationTubular formationWorkautoinflammatorycell typecomparativecytokineeffective therapyefficacy testingin vivoinhibitor/antagonistinterestkidney cellkidney dysfunctionmortalitymouse modelnew therapeutic targetpodocytepreclinical efficacypreventrenal damageresponserestraintside effecttranscription factor
中文摘要
摘要
抗体介导的肾小球肾炎(antibody-mediated glomerulonephritis,AGN)是自身免疫性肾脏疾病的一种临床表现。
引人注目的是,AGN是美国肾功能不全的第二大原因,占总肾功能不全的20 - 30%,
失败案例对免疫抑制药物的反应往往不充分,并与显着副作用相关
方面的影响.肾的肾小球和肾小管室中的慢性炎症导致组织损伤,
最终导致不可逆的肾功能丧失。新出现的数据表明促炎细胞因子IL-
17在AGN发病机制中的作用。IL-17领域的主要焦点一直是IL-17产生细胞如何
产生,而对IL-17下游信号的调节知之甚少。
相关组织细胞类型。我们的新数据显示,在AGN小鼠模型中证实了IL-17受体信号传导
是AGN发病所必需的。因此,我们将在这里集中于定义IL-17
信号传导机制和特定肾细胞类型的结果。理解这一点很重要,因为
组织损伤发生在局部,限制这种损伤的干预措施在临床上对治疗非常有价值。
终末器官损伤是AGN的特征具体而言,该提案围绕
理解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
确定了两种RNA结合蛋白(RBP),Regnase-1和Arid5a,它们以相反的方式起作用,
分别阴性和阳性控制IL-17信号传导。与AGN特别相关的是,
控制IL-17依赖的脂质运载蛋白-2的表达,脂质运载蛋白-2发挥强有力的肾损伤特性。我们
中心假设是Regnase-1通过限制脂运载蛋白-2在AGN中的表达来限制AGN的发育。
肾炎性肾在目标1中,我们将确定选择性Regnase-1缺乏对肾脏居民的影响。
足细胞和RTEC。目的2将定义参与调节IL-17信号转导的信号传导事件,
小鼠和人类足细胞和RTEC。此外,还将评价治疗小鼠的临床前疗效
在AGN中使用Arid5a抑制剂,我们预测这将通过以下途径增加对IL-17信号传导的抑制:
Regnase-1。这些研究将促进我们对致病性IL-17信号传导在肿瘤细胞中如何调节的理解。
促进终末器官损害。此外,这项工作可能揭示新的药物靶点,在IL-
可用于治疗其他慢性肾脏中IL-17驱动的终末器官损伤的IL-17信号通路
涉及这种细胞因子的疾病。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
RNA binding proteins in end-organ autoimmune pathology
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依托单位:
海外基金