IFN-Is at the interface of Innate and Adapative Immunity
IFN-Is 位于先天免疫和适应性免疫的界面
基本信息
- 批准号:7391145
- 负责人:
- 金额:$ 30.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-04-15 至 2011-03-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAntigen-Presenting CellsAntiviral AgentsAppendixAreaBindingBiochemicalBiochemical GeneticsBiologicalCell NucleusCellsClassComplexCytokine Inducible SH2-Containing ProteinDendritic CellsExhibitsFamilyFibroblastsGene ExpressionGene TargetingGenesHistocompatibility Antigens Class IIHumanIFNAR1 geneImmuneImmune responseImmunityIn VitroInterferon Type IInterferon Type IIInterferon-alphaInterferon-betaInterferonsInvestigationKineticsKnockout MiceMHC Class II GenesMediatingModificationMusNuclear ImportNumbersPathogenesisPathway interactionsPhosphoric Monoester HydrolasesPlayPrincipal InvestigatorPropertyProteinsRecruitment ActivityRegulationRoleSignal PathwaySignal TransductionSystemic Lupus ErythematosusTissuesTranscriptional ActivationTyrosine PhosphorylationUbiquitinUp-RegulationVirusVirus Diseasescytokinemacrophagemanprogramsprotein inhibitors of activated STATreceptorresponsetranscription factortype I interferon receptorubiquitin-protein ligase
项目摘要
DESCRIPTION (provided by applicant): Interferons (IFNs), first identified for their potent antiviral activity, can be divided into two major classes. Of these, type II or immune IFN (a.k.a. IFN-gamma) has earned much notoriety, but the type I IFNs (IFN-Is; e.g., IFN-alpha, IFN-beta, etc.) represent a much larger and complex family. Consistent with this, viruses have evolved numerous strategies to thwart IFN-I activity. More recently, IFN-Is have also achieved some celebrity with the recognition that they are the major effector cytokine secreted by plasmacvtoid dendritic cells (pDCs, a.k.a. "Natural IFN-I Producing Cells"). These IFN-Is then regulate aspects of both innate and adaptive immunity. There is also intriguing new evidence that IFN-Is and pDCs play an important role in the pathogenesis of Systemic Lupus Erythematosis (SLE).
Like other cytokines, IFN-Is induce their potent activity through the induction of new genes. Characterization of the ability of IFN-alpha to rapidly induce genes led to the identification of Stat1 and Stat2, the first two STAT transcription factors. These STATs are recruited to the type I IFN receptor (IFNAR) by unknown mechanisms, whereupon they become activated (by tyrosine phosphorylation), dimerize, translocate to the nucleus and activate genes. In contrast, IFN-gamma transduces its signals solely through Stat1, albeit with differing kinetics.
To determine the unique role Stat2 plays in the biological response to IFN-Is, Stat2 knockout mice were generated. These mice were highly susceptible to viral infection and partially unresponsive to IFN-Is. Unexpectedly, they exhibited tissue-specific differences in IFN-I stimulated Statl activation and a loss in the normal regulation of the Major Histocompatibility Complex class II (MHC-II). These observations highlight the important role type I IFNs play in regulating innate and adaptive immunity. To understand how IFN-Is mediate their many potent effects we propose to:
1. Determine how STATs are activated at the type I IFN receptor, including tissue specific differences.
2. Determine the unique role Stat2 exhibits in regulating MHC-II expression in macrophages
3. Explore the role SUMOylation may play in regulating the kinetics of IFN stimulated STATs.
描述(由申请人提供):干扰素(IFN),首先被鉴定为有效的抗病毒活性,可分为两大类。其中,II型或免疫IFN(a.k.a. IFN-γ)已经赢得了很多恶名,但是I型IFN(IFN-1;例如,IFN-α、IFN-β等)代表了一个更大更复杂的家庭与此一致,病毒已经进化出许多策略来阻碍IFN-1活性。最近,IFN-1也获得了一些知名度,认识到它们是由浆细胞样树突细胞(pDC,a.k.a.“天然IFN-I产生细胞”)。这些IFN-I然后调节先天免疫和适应性免疫两者的方面。还有有趣的新证据表明,IFN-1和pDC在系统性红斑狼疮(SLE)的发病机制中起重要作用。
与其他细胞因子一样,IFN-1通过诱导新基因来诱导其有效活性。IFN-α快速诱导基因的能力的表征导致了前两个STAT转录因子Stat 1和Stat 2的鉴定。这些STAT通过未知的机制被募集到I型IFN受体(IFNAR),于是它们被激活(通过酪氨酸磷酸化)、二聚化、易位到细胞核并激活基因。相反,IFN-γ仅通过Stat 1转导其信号,尽管动力学不同。
为了确定Stat 2在对IFN-1的生物学应答中发挥的独特作用,产生了Stat 2敲除小鼠。这些小鼠对病毒感染高度敏感,并且对IFN-1部分无反应。出乎意料的是,它们在IFN-1刺激的Stat 1活化和II类主要组织相容性复合物(MHC-II)的正常调节中表现出组织特异性差异。这些观察结果强调了I型IFN在调节先天性和适应性免疫中的重要作用。为了了解IFN-1是如何介导其许多有效作用的,我们建议:
1.确定STAT如何在I型IFN受体上被激活,包括组织特异性差异。
2.确定Stat 2在调节巨噬细胞MHC-II表达中的独特作用
3.探索SUMO化在调节IFN刺激的STAT的动力学中可能发挥的作用。
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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CHRISTIAN W SCHINDLER其他文献
CHRISTIAN W SCHINDLER的其他文献
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{{ truncateString('CHRISTIAN W SCHINDLER', 18)}}的其他基金
Genetic characterization of the murine type I Interferon locus
小鼠 I 型干扰素基因座的遗传特征
- 批准号:
8780594 - 财政年份:2013
- 资助金额:
$ 30.42万 - 项目类别:
Genetic characterization of the murine type I Interferon locus
小鼠 I 型干扰素基因座的遗传特征
- 批准号:
8623890 - 财政年份:2013
- 资助金额:
$ 30.42万 - 项目类别:
Probing the Innate Response to 3', 5'-cyclic Diguanylate (c-diGMP)
探索对 3, 5-环二鸟苷酸 (c-diGMP) 的先天反应
- 批准号:
8274633 - 财政年份:2011
- 资助金额:
$ 30.42万 - 项目类别:
Probing the Innate Response to 3', 5'-cyclic Diguanylate (c-diGMP)
探索对 3, 5-环二鸟苷酸 (c-diGMP) 的先天反应
- 批准号:
8176709 - 财政年份:2011
- 资助金额:
$ 30.42万 - 项目类别:
IFN-Is at the interface of Innate and Adapative Immunity
IFN-Is 位于先天免疫和适应性免疫的界面
- 批准号:
7916939 - 财政年份:2009
- 资助金额:
$ 30.42万 - 项目类别:
Characterization of the Innate Immune Response to Crystalline Silica
对结晶二氧化硅的先天免疫反应的表征
- 批准号:
7512740 - 财政年份:2009
- 资助金额:
$ 30.42万 - 项目类别:
Characterization of the Innate Immune Response to Crystalline Silica
对结晶二氧化硅的先天免疫反应的表征
- 批准号:
7846828 - 财政年份:2009
- 资助金额:
$ 30.42万 - 项目类别:
FLUORESCENCE-ACTIVATED CELL SORTER: STEM CELLS: ADULT HUMAN, ADULT MOUSE
荧光激活细胞分选仪:干细胞:成年人类、成年小鼠
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6973147 - 财政年份:2004
- 资助金额:
$ 30.42万 - 项目类别:
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