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:
- 金额:$ 50.69万
- 依托单位:
- 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:
- 关键词:AddressAntibodiesAttentionAutoimmuneAutoimmunityBindingBiologicalBiological MarkersBiological ModelsBiological Response ModifiersBlocking AntibodiesBone MarrowCCAAT-Enhancer-Binding ProteinsCCAAT-enhancer-binding protein-deltaCell Cycle KineticsCellsChimera organismDataDevelopmentDiabetes MellitusDiagnosticDiseaseDrug TargetingEpithelialEquilibriumEvaluationEventExhibitsExperimental Autoimmune EncephalomyelitisFoundationsGene ExpressionGenesGenetic TranscriptionGenetic TranslationGlomerulonephritisGoalsImmune responseImmune systemImpairmentInfectionInflammationInflammatoryInterleukin-17Interleukin-6InterleukinsLCN2 geneLeadLinkLymphocyteMediatingMediator of activation proteinMesenchymalMessenger RNAModelingMolecularMultiple SclerosisMusPathogenesisPathogenicityPathologicPathologyPathway interactionsPatientsProcessProtein FamilyProteinsPsoriasisRNA-Binding ProteinsRefractoryRegulationResistanceRiskRoleSignal TransductionSignaling MoleculeSystemT-LymphocyteTherapeuticThermogenesisTissuesTranscriptTranslationscell typeclinical efficacyimmunopathologyin vivointerestmRNA ExpressionmRNA Stabilitymembermicroorganismnovelpathogenpre-clinicalreceptortherapeutic targettranscription factorγδ 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
炎症状况。近年来,针对IL-17通路的生物药物已
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
炎症性疾病状况。我们长期以来一直有兴趣了解
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。 IL-17 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)。白细胞介素17
还激活许多控制 mRNA 稳定性的转录后机制
和翻译。筛选涉及 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
病理。引人注目的是,缺乏这种 RBP 的细胞在 IL-17 方面表现出明显受损
信号传导,特别是 NF-κB 和 C/EBPδ 的激活。在体内,缺乏这种 RBP 的小鼠
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)
自身免疫性肾小球肾炎。该应用程序的目标是定义
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)。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Sarah L Gaffen其他文献
Sarah L Gaffen的其他文献
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{{ truncateString('Sarah L Gaffen', 18)}}的其他基金
Host and Fungal Regulation of Type 17 Immunity to Oral Candidiasis
17 型口腔念珠菌病免疫的宿主和真菌调节
- 批准号:
10551422 - 财政年份:2022
- 资助金额:
$ 50.69万 - 项目类别:
Host and Fungal Regulation of Type 17 Immunity to Oral Candidiasis
17 型口腔念珠菌病免疫的宿主和真菌调控
- 批准号:
10673918 - 财政年份:2022
- 资助金额:
$ 50.69万 - 项目类别:
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
- 批准号:
10524055 - 财政年份:2019
- 资助金额:
$ 50.69万 - 项目类别:
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
- 批准号:
10065494 - 财政年份:2019
- 资助金额:
$ 50.69万 - 项目类别:
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
- 批准号:
9913154 - 财政年份:2019
- 资助金额:
$ 50.69万 - 项目类别:
IL-23/STAT3-Driven Oral Immune Responses to Candida albicans
IL-23/STAT3 驱动的针对白色念珠菌的口腔免疫反应
- 批准号:
8977508 - 财政年份:2014
- 资助金额:
$ 50.69万 - 项目类别:
Negative Control of IL-17R Signaling: Implications for Fungal Immunity
IL-17R 信号传导的阴性控制:对真菌免疫的影响
- 批准号:
8976213 - 财政年份:2014
- 资助金额:
$ 50.69万 - 项目类别:
Negative Control of IL-17R Signaling: Implications for Fungal Immunity
IL-17R 信号传导的阴性控制:对真菌免疫的影响
- 批准号:
8692225 - 财政年份:2014
- 资助金额:
$ 50.69万 - 项目类别:
IL-23/STAT3-Driven Oral Immune Responses to Candida albicans
IL-23/STAT3 驱动的针对白色念珠菌的口腔免疫反应
- 批准号:
9193080 - 财政年份:2014
- 资助金额:
$ 50.69万 - 项目类别:
IL-23/STAT3-Driven Oral Immune Responses to Candida albicans
IL-23/STAT3 驱动的针对白色念珠菌的口腔免疫反应
- 批准号:
8611195 - 财政年份:2014
- 资助金额:
$ 50.69万 - 项目类别:
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