The TLR4/MD-2 signaling pathway in gonoccocal disease
淋球菌疾病中的 TLR4/MD-2 信号通路
基本信息
- 批准号:7764287
- 负责人:
- 金额:$ 29.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-25 至 2014-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAffinity ChromatographyAppearanceBackBackcrossingsBacterial InfectionsBaculovirusesBindingBiochemicalBiologyBone MarrowBreedingBudgetsC-terminalCD14 AntigenCationsCell LineCell surfaceCellsCircular DichroismCleaved cellCo-ImmunoprecipitationsCollaborationsComplexConfocal MicroscopyCrystallographyCysteineCytoplasmic TailDNADataDefectDiseaseDistalEctopic PregnancyEndotoxinsEngineeringEscherichia coliEventExtracellular ProteinFundingFutureGel ChromatographyGeneticGenetic PolymorphismGenitourinary systemGoalsGonorrheaGram-Negative BacteriaGrowthHabitsHumanI-kappa B ProteinsIL6 geneIRAK4 geneImmunityImmunoglobulin GImmunomodulatorsIn VitroInbred BALB C MiceIncubatedIndividualInfectionInfertilityInflammationInflammatoryInsectaInterferonsInterleukin-1 ReceptorsIon-Exchange Chromatography ProcedureKnock-in MouseKnock-outKnockout MiceLeadLesionLigand BindingLigandsLipid ALipidsLipopolysaccharidesMeasuresMediatingMediator of activation proteinMembraneMolecularMolecular ConformationMolecular GeneticsMolecular Sieve ChromatographyMolecular StructureMusNatureNeisseria gonorrhoeaeOutcomePathway interactionsPatientsPelvic Inflammatory DiseasePelvic PainPelvisPhasePhenotypePhosphorylationPhysiologicalPlayPost-Translational Protein ProcessingProductionProteinsRecruitment ActivityReporterRobin birdRoleSamplingScreening procedureSignal PathwaySignal TransductionSignaling MoleculeSingle Nucleotide PolymorphismSpeedStructureSyndromeSystemTLR1 geneTLR2 geneTLR4 geneTechnologyTestingThrombinToll-like receptorsTransfectionTubal PregnancyUnited States National Institutes of HealthUpper armVaccine TherapyVaginaVariantWomanWorkadapter proteinbasechronic pelvic paincongenic breedingcytokinedimerhigh riskhuman TYRP1 proteinin vivointerestlipooligosaccharidemacrophagemouse modelnovelpreventreceptorreceptor functionresponsesexually activesmall moleculesuccesstoll-like receptor 4
项目摘要
Neisseria gonorrhoeae causes a variety of disease syndromes including pelvic iniflammatory disease
[PID]. PID can lead to chronic pelvic pain, ectopic pregnancy and infertility. Those syndromes caused by N.
gonorrhoeae have, in common, intense inflammation mediated by inflammatory cells. This inflammation is
primarily the result of the interaction of neisserial LPS (LOS) v\/ith the LPS receptor complex: TLR4 and MD-
2. The components of the LPS receptor were identified a decade ago, yet it is still poorly understood, 1)
how the binding of lipid A to MD-2 results in the formation of an active receptor complex, and, 2) how a
signal is subsequently transmitted resulting in the production of proinflammatory mediators such as TNFa
and IL-ip. In this proposal, we describe plans to determine how MD-2, once bound to lipid A,
acquires the ability to activate TLR4. The approach builds upon our success in purifying MD-2, a small
molecule with 7 cysteine residues that has a notorious tendency to form inactive multimers. We plan to
resolve the structure of MD-2 in the absence and presence of activating ligand, and in the presence of TLR4
to determine what conformational changes in TLR4/MD-2 induce signaling. We shall then focus our
energies on TLR4-related adapter molecules involved in cell signaling. We have previously analyzed 5
single nucleotide polymorphisms (SNPs) in the adapter protein known as Mai (used by both TLR2 and
TLR4). Two SNPs are of great interest: S180L and D96N. As part of another NIH funded project, we have
begun to generate mice carrying these lesions and are screening patient samples for the presence of D96N.
Mai knock out mice and knock-in mice carrying the mouse equivalent of D96N or S180L will be tested in the
mouse model of GC infection by Dr. Ingalls (PI, project 2). We will perform similar molecular genetic studies
of the 6 known SNPs in MyD88, the downstream adapter that interacts with Mai and an important adapter for
at least 8 of the TLRs. Should any of the SNPs display a phenotype, we will generate knock-in mice and
screen patient samples to determine relevancy. Finally, we will attempt to define the interaction of Mai and
MyD88 by biochemical means, culminating in an attempt to co crystallize the Mal/MyD88 dimer.
淋病奈瑟菌可引起多种疾病综合征,包括盆腔炎性疾病
[PID]。PID可导致慢性盆腔疼痛、异位妊娠和不孕。N.
淋病通常具有由炎性细胞介导的强烈炎症。这种炎症是
主要是奈瑟菌LPS(LOS)与LPS受体复合物:TLR 4和MD-1相互作用的结果。
2. LPS受体的组成部分在十年前就被发现了,但人们对它的了解仍然很少,1)
脂质A与MD-2的结合如何导致活性受体复合物的形成,以及,2)
信号随后被传递,导致促炎介质如TNF α的产生
和IL-IP。在这个提议中,我们描述了确定MD-2一旦与脂质A结合,
获得激活TLR 4的能力。该方法建立在我们成功纯化MD-2的基础上,
具有7个半胱氨酸残基的分子,其具有形成无活性多聚体的臭名昭著的倾向。我们计划
解析MD-2在不存在和存在活化配体以及存在TLR 4的情况下的结构
以确定TLR 4/MD-2中的何种构象变化诱导信号传导。然后我们将集中我们的
参与细胞信号传导的TLR 4相关衔接分子上的能量。我们之前分析了5个
被称为Mai的衔接蛋白中的单核苷酸多态性(SNP)(由TLR 2和
TLR4)。两个SNPs是非常感兴趣的:S180 L和D96 N。作为NIH资助的另一个项目的一部分,
开始产生携带这些病变的小鼠,并筛选患者样本中是否存在D96 N。
携带小鼠等同物D96 N或S180 L的Mai敲除小鼠和敲入小鼠将在实验室中进行测试。
Ingalls博士的GC感染小鼠模型(PI,项目2)。我们将进行类似的分子遗传学研究
在MyD 88中的6个已知SNPs中,与Mai相互作用的下游衔接子和与Mai相互作用的重要衔接子是MyD 88中的一个。
至少8个TLR。如果任何SNP显示表型,我们将产生敲入小鼠,
筛选患者样本以确定相关性。最后,我们将尝试定义Mai和
MyD 88,最终尝试共结晶Mal/MyD 88二聚体。
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 }}
Douglas T Golenbock其他文献
The NALP3 inflammasome is involved in the innate immune response to amyloid-β
NALP3 炎性体参与对淀粉样β的固有免疫应答
- DOI:
10.1038/ni.1636 - 发表时间:
2008-07-11 - 期刊:
- 影响因子:27.600
- 作者:
Annett Halle;Veit Hornung;Gabor C Petzold;Cameron R Stewart;Brian G Monks;Thomas Reinheckel;Katherine A Fitzgerald;Eicke Latz;Kathryn J Moore;Douglas T Golenbock - 通讯作者:
Douglas T Golenbock
Adjuvants and their signaling pathways: beyond TLRs
佐剂及其信号通路:超越 TLRs
- DOI:
10.1038/ni1203-1162 - 发表时间:
2003-12-01 - 期刊:
- 影响因子:27.600
- 作者:
Egil Lien;Douglas T Golenbock - 通讯作者:
Douglas T Golenbock
Innate immunity in Alzheimer's disease
阿尔茨海默病中的先天免疫
- DOI:
10.1038/ni.3102 - 发表时间:
2015-02-17 - 期刊:
- 影响因子:27.600
- 作者:
Michael T Heneka;Douglas T Golenbock;Eicke Latz - 通讯作者:
Eicke Latz
Douglas T Golenbock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('Douglas T Golenbock', 18)}}的其他基金
Innate Immune Mechanisms Governing Subclinical Malaria in Children
控制儿童亚临床疟疾的先天免疫机制
- 批准号:
10460703 - 财政年份:2022
- 资助金额:
$ 29.27万 - 项目类别:
Neisseria gonorrhoeae exploits host interferon epsilon to establish infection in the female urogenital tract
淋病奈瑟菌利用宿主干扰素ε在女性泌尿生殖道中建立感染
- 批准号:
10655520 - 财政年份:2021
- 资助金额:
$ 29.27万 - 项目类别:
Neisseria gonorrhoeae exploits host interferon epsilon to establish infection in the female urogenital tract
淋病奈瑟菌利用宿主干扰素ε在女性泌尿生殖道中建立感染
- 批准号:
10317367 - 财政年份:2021
- 资助金额:
$ 29.27万 - 项目类别:
Neisseria gonorrhoeae exploits host interferon epsilon to establish infection in the female urogenital tract
淋病奈瑟菌利用宿主干扰素ε在女性泌尿生殖道中建立感染
- 批准号:
10435574 - 财政年份:2021
- 资助金额:
$ 29.27万 - 项目类别:
Inflammasome activation in modulation of Alzheimer's Disease by alcohol
酒精调节阿尔茨海默氏病中炎症小体的激活
- 批准号:
10673213 - 财政年份:2020
- 资助金额:
$ 29.27万 - 项目类别:
Inflammasome activation in modulation of Alzheimer's Disease by alcohol
酒精调节阿尔茨海默氏病中炎症小体的激活
- 批准号:
10471334 - 财政年份:2020
- 资助金额:
$ 29.27万 - 项目类别:
Inflammasome activation in modulation of Alzheimer's Disease by alcohol
酒精调节阿尔茨海默氏病中炎症小体的激活
- 批准号:
10264088 - 财政年份:2020
- 资助金额:
$ 29.27万 - 项目类别:
Mechanisms of type I IFN enhanced gonococcal infection
I型干扰素增强淋球菌感染的机制
- 批准号:
9979327 - 财政年份:2020
- 资助金额:
$ 29.27万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 29.27万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 29.27万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 29.27万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 29.27万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 29.27万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 29.27万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 29.27万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 29.27万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 29.27万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 29.27万 - 项目类别:
Studentship