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

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)最初因其有效的抗病毒活性而被鉴定,可分为两大类。其中,II 型或免疫 IFN(又名 IFN-γ)已声名狼藉,但 I 型 IFN(IFN-Is;例如 IFN-α、IFN-β 等)代表了一个更大且复杂的家族。与此相一致的是,病毒已经进化出多种策略来阻止 IFN-I 活性。最近,IFN-Is 也引起了一些关注,人们认识到它们是类浆树突状细胞(pDC,又名“天然 IFN-I 产生细胞”)分泌的主要效应细胞因子。然后,这些 IFN-Is 调节先天免疫和适应性免疫的各个方面。还有有趣的新证据表明 IFN-Is 和 pDC 在系统性红斑狼疮 (SLE) 的发病机制中发挥着重要作用。 与其他细胞因子一样,IFN-Is 通过诱导新基因来诱导其有效活性。 IFN-α 快速诱导基因能力的表征导致了 Stat1 和 Stat2(前两个 STAT 转录因子)的鉴定。这些 STAT 通过未知机制被招募到 I 型干扰素受体 (IFNAR),随后它们被激活(通过酪氨酸磷酸化)、二聚化、易位到细胞核并激活基因。相比之下,IFN-gamma 仅通过 Stat1 转导其信号,尽管动力学不同。 为了确定 Stat2 在 IFN-Is 生物反应中发挥的独特作用,我们培育了 Stat2 敲除小鼠。这些小鼠对病毒感染高度敏感,并且对 IFN-Is 部分无反应。出乎意料的是,它们在 IFN-I 刺激的 Stat1 激活方面表现出组织特异性差异,并且在主要组织相容性复合物 II 类 (MHC-II) 的正常调节方面丧失。这些观察结果强调了 I 型干扰素在调节先天性和适应性免疫中发挥的重要作用。为了了解 IFN-Is 如何介导其许多有效作用,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Stat2在调节巨噬细胞MHC-II表达中所表现出的独特作用 3. 探索SUMO化在调节IFN刺激的STATs动力学中可能发挥的作用。

项目成果

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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: DIABETES
荧光激活细胞分选仪:糖尿病
  • 批准号:
    6973150
  • 财政年份:
    2004
  • 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
  • 批准号:
    6973147
  • 财政年份:
    2004
  • 资助金额:
    $ 30.42万
  • 项目类别:
FLUORESCENCE-ACTIVATED CELL SORTER: AIDS
荧光激活细胞分选仪:艾滋病
  • 批准号:
    6973148
  • 财政年份:
    2004
  • 资助金额:
    $ 30.42万
  • 项目类别:

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