Mechanisms of STING-driven autoinflammation

STING 驱动的自身炎症机制

基本信息

项目摘要

Cyclic GMP-AMP synthase (cGAS) detects foreign DNA during infection or self-DNA leading to autoinflammatory diseases such as Aicardi-Goutieres syndrome. cGAS signals via STING, a receptor for cyclic GMP-AMP generated by cGAS. A series of gain-of-function mutations resulting in constitutive activation of STING have been associated with a debilitating autoinflammatory disease called STING-Associated- Vasculopathy with onset in Infancy (SAVI). SAVI patients suffer from severe vasculitic lesions and interstitial lung disease (ILD) and frequently succumb to respiratory failure. Like the lung conditions associated with other autoimmune diseases such as rheumatoid arthritis and systemic sclerosis, very little is known about the mechanisms that promote inflammation in these patients. To gain insights into the mechanisms of STING driven inflammation in the lung, we have developed a murine model for the most common SAVI mutation, STINGV154M (VM), and found that mice heterozygous for this mutation develop immune abnormalities and lung disease. Lung endothelial cells are among the highest STING-expressing cells in the lung and based on our preliminary data we believe that auto-inflammation in the VM lung results from the direct effects of the SAVI mutation on “initiator” radioresistant cells (endothelial cells, and/or fibroblasts) resulting in stromal cell activation, differentiation, chemokine production and expansion. Lymphocytes (VM or WT) are then recruited to the lung. The recruited effector T cells further promote the pathogenic activity of both radioresistant cells and myeloid cells, leading to chronic inflammation; IFN plays a key role in this process. How the VM SAVI allele mediate disease pathogenesis in stromal cells remains unknown. We will focus on STING activation in endothelial cells and how these events lead to lymphocyte recruitment, activation and pathology. Aim 1 will determine the lymphocyte- independent effect of SAVI mutations on lung innate immune function. Aim 2 will define the role of infiltrating T cells in the development of VM ILD while Aim 3 will define VM-driven signaling events in ECs and the impact of STING-targeted therapeutics on ILD. There is an urgent need to identify better therapies for patients afflicted with autoimmune and autoinflammatory lung disorders and the studies proposed in this application should provide critical insights that will enable us to design the best therapies. Further, these studies will also provide an opportunity to study the impact of STING activation on stromal cell types more generally, an emerging area of research as STING activity in endothelial cells has recently been linked to the development of severe COVID19.
环GMP-AMP合成酶(cGAS)在感染过程中检测外源DNA或自身DNA导致

项目成果

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Katherine A. Fitzgerald其他文献

Quantifying and Mitigating Motor Phenotypes Induced by Quantifying and Mitigating Motor Phenotypes Induced by Antisense Oligonucleotides in the Central Nervous System Antisense Oligonucleotides in the Central Nervous System
量化和减轻中枢神经系统中反义寡核苷酸诱导的运动表型 量化和减轻中枢神经系统中反义寡核苷酸诱导的运动表型
  • DOI:
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Michael P. Moazami;Julia M. Rembetsy;Feng Wang;P. M. Krishnamurthy;Alexandra Weiss;M. Marosfoi;Robert M. King;M. Motwani;H. Gray;Katherine A. Fitzgerald;Robert H Brown;Jonathan K. Watts
  • 通讯作者:
    Jonathan K. Watts
Lipopolysaccharide sensing on the inside
内部的脂多糖感应
  • DOI:
    10.1038/nature12556
  • 发表时间:
    2013-09-04
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    Vijay A. K. Rathinam;Katherine A. Fitzgerald
  • 通讯作者:
    Katherine A. Fitzgerald
α位に種々の置換基を有するジチオアセタール類の選択的電解フッ素化
α位具有各种取代基的二硫缩醛的选择性电氟化
  • DOI:
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Sarah M. McWhirter;Roman Barbalat;Kathryn M. Monroe;Mary F. Fontana;Mamoru Hyodo;Nathalie T. Joncker;Ken J. Ishi;Shizuo Akira;Marco Colonna;Zhijian J. Chen;Katherine A. Fitzgerald;Yoshihiro Hayakawa;and Russell E. Vance;小手石泰康・野正樹・山口和也・鈴木晋一郎;両角俊也・尹斌・稲木信介・淵上寿雄
  • 通讯作者:
    両角俊也・尹斌・稲木信介・淵上寿雄
Long non-coding RNAs: definitions, functions, challenges and recommendations
长链非编码 RNA:定义、功能、挑战与建议
  • DOI:
    10.1038/s41580-022-00566-8
  • 发表时间:
    2023-01-03
  • 期刊:
  • 影响因子:
    90.200
  • 作者:
    John S. Mattick;Paulo P. Amaral;Piero Carninci;Susan Carpenter;Howard Y. Chang;Ling-Ling Chen;Runsheng Chen;Caroline Dean;Marcel E. Dinger;Katherine A. Fitzgerald;Thomas R. Gingeras;Mitchell Guttman;Tetsuro Hirose;Maite Huarte;Rory Johnson;Chandrasekhar Kanduri;Philipp Kapranov;Jeanne B. Lawrence;Jeannie T. Lee;Joshua T. Mendell;Timothy R. Mercer;Kathryn J. Moore;Shinichi Nakagawa;John L. Rinn;David L. Spector;Igor Ulitsky;Yue Wan;Jeremy E. Wilusz;Mian Wu
  • 通讯作者:
    Mian Wu
A pan-family screen of nuclear receptors in immunocytes reveals ligand-dependent inflammasome control
  • DOI:
    10.1016/j.immuni.2024.10.010
  • 发表时间:
    2024-12-10
  • 期刊:
  • 影响因子:
  • 作者:
    Yutao Wang;Yanbo Zhang;Kyungsub Kim;Jichang Han;Daniel Okin;Zhaozhao Jiang;Liang Yang;Arun Subramaniam;Terry K. Means;Frank O. Nestlé;Katherine A. Fitzgerald;Gwendalyn J. Randolph;Cammie F. Lesser;Jonathan C. Kagan;Diane Mathis;Christophe Benoist
  • 通讯作者:
    Christophe Benoist

Katherine A. Fitzgerald的其他文献

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{{ truncateString('Katherine A. Fitzgerald', 18)}}的其他基金

Radioresistant Innate Immunity in SAVI Tissue-Specific Autoinflammation
SAVI 组织特异性自身炎症中的抗辐射先天免疫
  • 批准号:
    10752556
  • 财政年份:
    2023
  • 资助金额:
    $ 83.72万
  • 项目类别:
9th Annual meeting of the International Cytokine and Interferon Society Meeting
国际细胞因子和干扰素学会第九届年会
  • 批准号:
    10389980
  • 财政年份:
    2021
  • 资助金额:
    $ 83.72万
  • 项目类别:
Training in the Molecular Basis of Autoimmunity and Autoinflammation
自身免疫和自身炎症的分子基础培训
  • 批准号:
    10201428
  • 财政年份:
    2018
  • 资助金额:
    $ 83.72万
  • 项目类别:
Training in the Molecular Basis of Autoimmunity and Autoinflammation
自身免疫和自身炎症的分子基础培训
  • 批准号:
    10442502
  • 财政年份:
    2018
  • 资助金额:
    $ 83.72万
  • 项目类别:
Training in the Molecular Basis of Autoimmunity and Autoinflammation
自身免疫和自身炎症的分子基础培训
  • 批准号:
    10712784
  • 财政年份:
    2018
  • 资助金额:
    $ 83.72万
  • 项目类别:
Regulation of Lupus by Cytosolic DNA Sensors
细胞质 DNA 传感器对狼疮的调节
  • 批准号:
    9229764
  • 财政年份:
    2017
  • 资助金额:
    $ 83.72万
  • 项目类别:
Characterization of Chromatin associated Long non-coding in immunity
免疫中染色质相关长非编码的表征
  • 批准号:
    8809301
  • 财政年份:
    2014
  • 资助金额:
    $ 83.72万
  • 项目类别:
Characterization of Chromatin associated Long non-coding in immunity
免疫中染色质相关长非编码的表征
  • 批准号:
    8966645
  • 财政年份:
    2014
  • 资助金额:
    $ 83.72万
  • 项目类别:
DNA sensors and associated signaling pathways in the innate immune response
先天免疫反应中的 DNA 传感器和相关信号通路
  • 批准号:
    8297717
  • 财政年份:
    2012
  • 资助金额:
    $ 83.72万
  • 项目类别:
DNA sensors and associated signaling pathways in the innate immune response
先天免疫反应中的 DNA 传感器和相关信号通路
  • 批准号:
    8606390
  • 财政年份:
    2012
  • 资助金额:
    $ 83.72万
  • 项目类别:

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