Distinguishing cytosolic sensing of DNA and cyclic dinucleotides in vivo
体内区分 DNA 和环状二核苷酸的胞质传感
基本信息
- 批准号:8606401
- 负责人:
- 金额:$ 23.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-02-01 至 2016-01-31
- 项目状态:已结题
- 来源:
- 关键词:Adaptor Signaling ProteinAddressAffectAllelesAmino AcidsArginineBacteriaBacterial InfectionsBacterial PhysiologyBeliefBindingCellsCommunicable DiseasesCytosolDNADataDefectDinucleoside PhosphatesDissectionExhibitsFaceGenesGerm LinesGoalsIRF3 geneImmuneImmune responseImmune systemImmunologyImmunotherapeutic agentInfectionIntegral Membrane ProteinIntentionInterferon Type IInterferonsKnock-in MouseKnockout MiceLegionella pneumophilaLigandsListeria monocytogenesMammalian CellMethodsModelingMolecularMorbidity - disease rateMusMutagenesisMutationMycobacterium tuberculosisNatureNucleic AcidsNucleotidesPathway interactionsPhosphotransferasesPoint MutationPoliciesProcessProductionProteinsPublishingRNAReagentResearch PersonnelResourcesRoleSecond Messenger SystemsSignal TransductionSting InjuryTBK1 geneTechniquesTestingVaccine AdjuvantVirulenceWorkbasebis(3&apos,5&apos)-cyclic diguanylic acidcell typecytokinedesignembryonic stem cellexperiencehomologous recombinationin vivoinduced pluripotent stem cellinterestmacrophagemicrobialmortalitymutantnovelpathogenpublic health relevancereceptorreconstitutionresearch studyresponsesecond messengersensorsuccesstooltranscription factor
项目摘要
DESCRIPTION (provided by applicant): The innate immune system detects infection via germ-line encoded receptors that recognize specific microbial ligands. We have been particularly interested in characterizing the innate immune response to unique nucleic acids produced by bacteria called cyclic dinucleotides. These nucleotides, which include c-di-GMP and c-di- AMP, are best known as key regulators of bacterial physiology. However, since they are not produced by mammalian cells, cyclic dinucleotides are ideal targets for innate immune recognition. Indeed, we found that the presence of cyclic dinucleotides in the host cell cytosol induces an innate immune response characterized by the production of important cytokines called type I interferons (IFNs). We recently found that the host protein STING is a direct innate immune sensor of cyclic dinucleotides. STING binds to cyclic dinucleotides in the cytosol and is essential for subsequent induction of a host type I interferon response. Interestingly, however, it
has also been shown that STING is essential for induction of the host interferon response to cytosolic DNA. Since STING is required for the IFN response to both DNA and cyclic dinucleotides, the field now faces a significant problem, namely, there is no way to determine in vivo whether interferon induction by any given bacterial pathogen is due to cytosolic recognition of DNA or cyclic dinucleotides. This is a critical issue since virtually all bacterial pathogens ar capable of producing both stimulatory ligands. To address this problem we identified a specific point mutation in STING (R231A) that selectively abolishes the IFN response to cyclic dinucleotides without affecting the cytosolic response to DNA. This mutant provides a unique tool for distinguishing the responses to DNA versus cyclic dinucleotides. In this application we propose to leverage our findings to pursue two specific aims: (1) Generate "knock-in" mice in which the gene encoding wild-type STING is replaced by a gene encoding a STING R231A mutant (2) Validate and test STING R231A knock-in mice using various inducers and infection models. We plan to distribute the STING R231A knock-in mice without restriction to investigators that request them. Our hope is that these mice will represent a unique and powerful reagent for the field and allow investigators to determine for any pathogen of interest whether induction of the host IFN response is via DNA or cyclic dinucleotides.
描述(由申请人提供):先天免疫系统通过识别特定微生物配体的生殖系编码受体检测感染。我们一直特别感兴趣的特征先天免疫反应的独特的核酸产生的细菌称为环状二核苷酸。这些核苷酸,包括c-di-GMP和c-di- AMP,是细菌生理学的关键调节剂。然而,由于环状二核苷酸不是由哺乳动物细胞产生的,因此它们是先天免疫识别的理想靶点。事实上,我们发现,在宿主细胞胞质溶胶中的环状二核苷酸的存在下诱导先天性免疫反应,其特征在于生产的重要的细胞因子称为I型干扰素(IFN)。我们最近发现,宿主蛋白STING是环二核苷酸的直接先天免疫传感器。STING与胞质溶胶中的环状二核苷酸结合,并且对于随后诱导宿主I型干扰素应答是必需的。有趣的是,它
还显示STING对于诱导宿主对胞质DNA的干扰素应答是必需的。由于STING是针对DNA和环状二核苷酸的IFN应答所必需的,因此该领域现在面临着一个重要的问题,即,没有办法在体内确定任何给定细菌病原体的干扰素诱导是否是由于DNA或环状二核苷酸的胞质识别。这是一个关键问题,因为几乎所有的细菌病原体都能够产生两种刺激配体。为了解决这个问题,我们确定了一个特定的点突变STING(R231 A),选择性地取消了IFN响应环状二核苷酸,而不影响细胞溶质响应DNA。该突变体提供了一种独特的工具来区分对DNA和环状二核苷酸的反应。在本申请中,我们提出利用我们的发现来追求两个具体目标:(1)产生“敲入”小鼠,其中编码野生型STING的基因被编码STING R231 A突变体的基因替换;(2)使用各种诱导剂和感染模型来鉴定和测试STING R231 A敲入小鼠。我们计划将STING R231 A基因敲入小鼠不受限制地分发给要求它们的研究者。我们的希望是,这些小鼠将代表该领域的一个独特的和强大的试剂,并允许研究人员确定任何感兴趣的病原体是否诱导宿主IFN应答是通过DNA或环状二核苷酸。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
RUSSELL E VANCE其他文献
RUSSELL E VANCE的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('RUSSELL E VANCE', 18)}}的其他基金
Dissection of Shigella pathogenesis in vivo using a new oral infection mouse model
使用新的口腔感染小鼠模型剖析志贺氏菌体内发病机制
- 批准号:
10098247 - 财政年份:2020
- 资助金额:
$ 23.48万 - 项目类别:
Dissection of Shigella pathogenesis in vivo using a new oral infection mouse model
使用新的口腔感染小鼠模型剖析志贺氏菌体内发病机制
- 批准号:
10681402 - 财政年份:2020
- 资助金额:
$ 23.48万 - 项目类别:
Dissection of Shigella pathogenesis in vivo using a new oral infection mouse model
使用新的口腔感染小鼠模型剖析志贺氏菌体内发病机制
- 批准号:
10268219 - 财政年份:2020
- 资助金额:
$ 23.48万 - 项目类别:
Dissection of Shigella pathogenesis in vivo using a new oral infection mouse model
使用新的口腔感染小鼠模型剖析志贺氏菌体内发病机制
- 批准号:
10464909 - 财政年份:2020
- 资助金额:
$ 23.48万 - 项目类别:
Distinguishing cytosolic sensing of DNA and cyclic dinucleotides in vivo
体内区分 DNA 和环状二核苷酸的胞质传感
- 批准号:
8434745 - 财政年份:2013
- 资助金额:
$ 23.48万 - 项目类别:
Host innate responses induced by intracellular bacteria and cyclic-di-nucleotides
由细胞内细菌和环二核苷酸诱导的宿主先天反应
- 批准号:
8234234 - 财政年份:2011
- 资助金额:
$ 23.48万 - 项目类别:
Macrophage transcriptional responses to Legionella pneumophila
巨噬细胞对嗜肺军团菌的转录反应
- 批准号:
8260351 - 财政年份:2009
- 资助金额:
$ 23.48万 - 项目类别:
Macrophage transcriptional responses to Legionella pneumophila
巨噬细胞对嗜肺军团菌的转录反应
- 批准号:
7799079 - 财政年份:2009
- 资助金额:
$ 23.48万 - 项目类别:
Macrophage transcriptional responses to Legionella pneumophila
巨噬细胞对嗜肺军团菌的转录反应
- 批准号:
8050136 - 财政年份:2009
- 资助金额:
$ 23.48万 - 项目类别:
Macrophage transcriptional responses to Legionella pneumophila
巨噬细胞对嗜肺军团菌的转录反应
- 批准号:
8454515 - 财政年份:2009
- 资助金额:
$ 23.48万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 23.48万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 23.48万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 23.48万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 23.48万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 23.48万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 23.48万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 23.48万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 23.48万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 23.48万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 23.48万 - 项目类别:
Research Grant