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cGAMP as an immunotransmitter of the interferon response to UV light

cGAMP as an immunotransmitter of the interferon response to UV light
cGAMP 作为干扰素对紫外线反应的免疫递质
批准号:
10215860
负责人:
Keith B. Elkon
金额:
$42.71万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-09-23 至 2023-08-31

项目摘要

项目成果

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中文摘要
翻译
项目摘要 该项目的长期目标是确定cGAS-STING途径的作用, 信使环二核苷酸cGAMP,作为IFN应答的局部和全身免疫递质 皮肤暴露于UVB光之后。此外,我们还试图确定这些观察结果的意义 在SLE的相关小鼠模型中。 SLE患者特征性地在外周血细胞中具有I型干扰素(IFN-I)特征, 相同的标记在损伤和非损伤皮肤中是显著的。虽然人们普遍认为, 免疫激活导致IFN-I应答向组织的传播,我们观察到, 暴露于紫外线(UVB),UVB不仅在皮肤中而且在血液中诱导IFN特征, 野生型小鼠的肾脏。由于我们观察到IFN-I在紫外线照射后不久产生需要DNA 激活的细胞质传感器cGAS,我们假设cGAMP,环二核苷酸的合成产物, cGAS本身是一种免疫递质,负责局部和全身传播IFN-1应答。 在这个提议中,我们探索了UVB刺激的cGAMP产生如何导致IFN信号的传播, 皮肤,检查对引流淋巴结中局部免疫应答的影响,并寻找cGAMP 在野生型和狼疮倾向菌株中依赖组织炎症。为了实现这些目标,我们 缺乏cGAS或ENPP 1(外核苷酸焦磷酸酶)的遗传修饰小鼠的优势 磷酸二酯酶-1,其在从细胞输出后水解cGAMP),并利用可以利用的试剂 操纵cGAS-STING途径。我们专门研究cGAMP转运蛋白:连接蛋白, SLC 19 A1和容量调节阴离子通道(VRAC)LRRC 8,以确定哪些转运蛋白控制 cGAMP扩散以及在什么条件下扩散。 这些研究的意义在于,它们将有助于确定遗传和分子机制 负责UVB诱导IFN-I,定义信号如何传播,并可能指示狼疮如何爆发 暴露于UVB后发生。此外,这项研究还集中在一种酶ENPP 1上, 以前在自身免疫的背景下进行了研究,如果证明是重要的,可以利用 治疗性地中止cGAMP扩散。这些研究可能会扭转系统性IFN-I导致的范式 皮肤干扰素信号由于我们已经在系统性狼疮患者的血液中检测到了cGAMP, 红斑狼疮(SLE),这些研究的结果将有很强的翻译意义。
英文摘要
Project Summary The long-term goals of this project are to determine the role of the cGAS-STING pathway and the messenger cyclic dinucleotide cGAMP, as a local and systemic immunotransmitter of the IFN response following skin exposure to UVB light. In addition, we seek to determine the significance of these observations in a relevant mouse model of SLE. SLE patients characteristically have a type I interferon (IFN-I) signature in peripheral blood cells and this same signature is prominent in lesional and non-lesional skin. While it is generally assumed that systemic immune activation leads to dissemination of the IFN-I response to tissues, we observed that, following a single exposure to ultraviolet light (UVB), UVB induces an IFN signature not only in the skin but also in the blood and kidneys of wild type mice. Since we observed that IFN-I produced soon after UV exposure requires the DNA activated cytoplasmic sensor cGAS, we hypothesize that cGAMP, the cyclic dinucleotide synthetic product of cGAS, is itself an immunotransmitter that is responsible for spreading the IFN-I response locally and systemically. In this proposal, we explore how UVB stimulated cGAMP production leads to spreading of the IFN signature in the skin, examine the effects on local immune response in the draining lymph nodes, and look for cGAMP dependent tissue inflammation in both wild type and lupus-prone strains. To achieve these Aims, we take advantage of genetically modified mice that are deficient in cGAS or ENPP1 (ectonucleotide pyrophosphatase phosphodiesterase-1 that hydrolyzes cGAMP after export from cells) and utilize reagents that can be exploited to manipulate the cGAS-STING pathway. We specifically interrogate the cGAMP transporters: connexins, SLC19A1 and the Volume Regulated Anion Channel (VRAC) LRRC8, to determine which transporters control cGAMP spreading and under what conditions. The significance of these studies are that they will help define the genetic and molecular mechanisms responsible for UVB induction of IFN-I, define how the signal spreads and, possibly, indicate how lupus flares occur following exposure to UVB. In addition, the research focuses on an enzyme, ENPP1, that has not previously been studied in the context of autoimmunity and, if shown to be important, could be harnessed therapeutically to abort cGAMP spreading. These studies could reverse the paradigm that systemic IFN-I causes the skin IFN signature. Since we have detected cGAMP in blood of a subset of patients with systemic lupus erythematosus (SLE), the results of these studies will have strong translational significance.
期刊论文(1)
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会议论文
DOI: 10.1038/s41581-022-00589-6
发表时间: 2022-09
期刊: Nature reviews. Nephrology
影响因子: --
作者: []
通讯作者:
Mechanisms of end organ damage in novel polygenic lupus models
  • 批准号:
    10007264
  • 项目类别:
  • 资助金额:
    $40.48万
  • 财政年份:
    2019
  • 负责人:
    Keith B. Elkon
  • 依托单位:
Link between Retroelements, Ro and Interferon Biology in Lupus
  • 批准号:
    9378686
  • 项目类别:
  • 资助金额:
    $23.23万
  • 财政年份:
    2017
  • 负责人:
    Keith B. Elkon
  • 依托单位:
Mechanisms of Ultraviolet Inflammation in Lupus
  • 批准号:
    8769410
  • 项目类别:
  • 资助金额:
    $26.1万
  • 财政年份:
    2014
  • 负责人:
    Keith B. Elkon
  • 依托单位:
Agonists and Antagonists of Neuropsychiatric Lupus
  • 批准号:
    7696866
  • 项目类别:
  • 资助金额:
    $34.94万
  • 财政年份:
    2009
  • 负责人:
    Keith B. Elkon
  • 依托单位:
海外基金