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
基本信息
- 批准号:10752556
- 负责人:
- 金额:$ 25.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-04 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdhesionsAllelesAreaAutoimmuneAutoimmune DiseasesAutomobile DrivingBone Marrow Stem CellBronchus-Associated Lymphoid TissueCell DeathCell LineCell SeparationCellsChimera organismCytosolDNADataDevelopmentDiseaseEmbryoEndothelial CellsEndotheliumExclusionExhibitsFibrosisFollow-Up StudiesGene ExpressionGenesGenetic TranscriptionGoalsHematopoieticHeterozygoteHost DefenseIRF3 geneImmuneIn VitroIndividualInfectionInflammationInflammatoryInnate Immune ResponseInterferonsInterstitial Lung DiseasesKnock-inLesionLinkLungLung diseasesLymphatic Endothelial CellsLymphocyteLymphopeniaMolecularMonitorMusMutationMyelogenousMyeloid CellsNatural ImmunityPathogenicityPathologyPathway interactionsPatientsPeripheralPhenotypePlayPopulationPulmonary FibrosisPulmonary InflammationRadiation ChimeraRag1 MouseReporterResearchResearch PersonnelResistanceRespiratory FailureRheumatoid ArthritisRoleSTING agonistsSeriesStimulator of Interferon GenesStromal CellsSystemic SclerodermaT-LymphocyteTBK1 geneTamoxifenTissuesVascular DiseasesVascular Endothelial Celladaptive immunityautoinflammationautoinflammatoryautoinflammatory diseasescell typecellular transductioncytokinedesigneffective therapyfibrotic lung diseasefunctional outcomesgain of function mutationgene functionhuman diseasein vivoinfancyinsightinterferon alpha receptorlymph nodesmicrobialmouse modelmutantneutrophilnovelpromoterpulmonary functionradioresistantreconstitutionrecruitsevere COVID-19skin lesionstem cellstherapeutic targettooltranscriptometreatment strategy
项目摘要
The cGas/STING cytosolic DNA sensing pathway detects microbial DNA and plays a critical role in host defense.
Growing evidence indicates that self-DNA that accumulates in the cytosol also engages cGAS to incite
inflammation. In addition, a series of gain-of-function mutations that result in constitutive activation of STING
have now been associated with a debilitating auto-inflammatory disease known as SAVI (STING-Associated-
Vasculopathy with onset in Infancy). These patients suffer from severe vasculitic lesions and progressive
interstitial lung disease (ILD), and frequently succumb to treatment-resistant ILD-associated with fibrosis. Similar
to the lung disorders associated with other inflammatory or fibrotic lung diseases, very little is known about the
pathogenic mechanisms in these patients. Thus, a better understanding of the mechanisms responsible for these
conditions is needed in order to develop more effective therapies. We have recently developed a murine model
for the most common SAVI mutation, STINGV154M (VM), and shown that these mice recapitulate the human
disease by a variety of criteria, including the development of inflammatory/fibrotic lung disease. These VM mice
provide a unique experimental tool for exploring the cell types and molecular mechanisms responsible for the
initiation and progression of fibrotic lung disease. Rag1-deficiency completely rescues VM mice from both lung
inflammation and lung fibrosis pointing to a critical role of the adaptive immunity in VM ILD. The role of STING
has been focused on myeloid cells and VM mice have an expanded and activated myeloid/neutrophil
compartment. However, radiation chimera studies have identified a key role for radioresistant cells in lung fibrosis
as lethally irradiated VM mice reconstituted with WT bone marrow stem cells develop extremely severe lung
disease even though these chimeras completely lack any VM-derived hematopoietic cells. Preliminary data
implicate lymphatic endothelial cells (LECs) as initiators of BALT formation in VM mice. The goal of this
application is to further explore the radioresistant innate immune cells that are directly or indirectly activated by
the VM mutation and define the mechanisms by which these cells promote lung inflammation. Our approach will
involve: (1) the in vivo analysis of a novel VM conditional KI line crossed to endothelial-restricted Cre deleter
strains and other relevant controls, (2) scRNAseq comparison of stromal populations including lymphatic and
vascular endothelial cells isolated from WT and VM mice; and (3) analysis of endothelial cells from VM and WT
mice following in vitro activation by the VM mutation or more conventional STING agonists. 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 most
relevant therapeutic targets. Further, these studies 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.
CGAS/STING胞质DNA传感通路检测微生物DNA,在宿主防御中发挥关键作用。
越来越多的证据表明,积累在细胞质中的自身DNA也参与cGAs的激发
发炎。此外,导致STIN结构性激活的一系列功能获得突变
现在都与一种称为SAVI(刺痛相关的)的衰弱自体炎症疾病有关
血管病变,起病于婴儿期)。这些患者患有严重的脉管炎损害和进展性
间质性肺疾病(ILD),并经常屈从于与纤维化相关的治疗耐药的ILD。类似
对于与其他炎症性或纤维性肺部疾病相关的肺部疾病,人们对
这些患者的致病机制。因此,更好地了解导致这些问题的机制
为了开发更有效的治疗方法,需要有适当的条件。我们最近开发了一种小鼠模型
对于最常见的SAVI突变STINGV154M(Vm),并表明这些小鼠重现了人类
疾病由多种标准决定,包括发展为炎症性/纤维性肺病。这些虚拟小鼠
为探索细胞类型和分子机制提供了一种独特的实验工具
纤维性肺病的发生和发展。Rag1缺陷完全拯救双肺VM小鼠
炎症和肺纤维化提示获得性免疫在VM ILD中起重要作用。刺痛的作用
一直专注于髓系细胞和VM小鼠具有扩大和激活的髓系/中性粒细胞
车厢。然而,辐射嵌合体研究已经确定了辐射抵抗细胞在肺纤维化中的关键作用。
用WT骨髓干细胞重建的VM小鼠在受到致死照射后出现极严重的肺损伤
即使这些嵌合体完全缺乏任何VM来源的造血细胞。初步数据
提示淋巴管内皮细胞(LECs)是Vm小鼠BALT形成的始动细胞。这样做的目的是
应用是进一步探索辐射抵抗的先天性免疫细胞直接或间接激活
Vm突变并确定这些细胞促进肺部炎症的机制。我们的方法将
涉及:(1)一种新的VM条件性KI细胞系与内皮限制性Cre缺失器交叉的体内分析
菌株和其他相关对照,(2)间质种群的scRNAseq比较,包括淋巴和
WT和Vm小鼠血管内皮细胞分离;(3)Vm和WT小鼠血管内皮细胞分析
由Vm突变或更传统的刺痛激动剂体外激活的小鼠。有一件急事
需要为患有自身免疫性和自体炎症性肺疾病的患者确定更好的治疗方法
本申请中提出的研究应该提供关键的见解,使我们能够设计出最
相关治疗靶点。此外,这些研究为研究刺痛的影响提供了机会。
更广泛地说,对基质细胞类型的激活是一个新兴的研究领域,如内皮细胞中的刺痛活性
细胞最近被认为与严重的COVID19的发展有关。
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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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:
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2022 - 期刊:
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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
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2011 - 期刊:
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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
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:
$ 25.13万 - 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:
$ 25.13万 - 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:
$ 25.13万 - 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:
$ 25.13万 - 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:
$ 25.13万 - 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:
$ 25.13万 - 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:
$ 25.13万 - 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
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DNA sensors and associated signaling pathways in the innate immune response
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- 批准号:
8606390 - 财政年份:2012
- 资助金额:
$ 25.13万 - 项目类别:
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