Regulation of MD-2 function and expression
MD-2 功能和表达的调节
基本信息
- 批准号:8493971
- 负责人:
- 金额:$ 33.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-07-01 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:AbbreviationsAcidsAcylationAffectAgonistAlbuminsAntigensBacteriaBindingBinding ProteinsBinding SitesBiochemicalBiologicalBuffersCCL4 geneCD14 geneCellsComplexDevelopmentDietDiseaseDivalent CationsE proteinEmbryoEndotoxinsEnvironmentEpithelial CellsEpitopesFatty AcidsGlycolipidsGram-Negative BacteriaGram-Negative Bacterial InfectionsHealthHost DefenseHumanHydrolaseIL8 geneImmuneImmune responseImmunomodulatorsInfectionInflammationInflammatory ResponseInterleukin-8InvadedIrrigationLabelLeadLigandsLipid ALipidsLipopolysaccharidesMembraneMicrobeModelingMonoclonal AntibodiesMusMyelogenousNeisseria meningitidisNonesterified Fatty AcidsNosePathologyPhosphate BufferPhospholipidsPhosphorylationPhysiologicalPhysiologyPlayPneumonic PlagueProliferatingPropertyReceptor ActivationRecombinantsRegulationRiskRoleSalineSerum AlbuminSignal TransductionSiteSodiumSodium ChlorideSolutionsSpecific qualifier valueStructureSurface PropertiesSystemTLR4 geneToll-like receptorsTranslatingVariantVirulencebactericidal permeability increasing proteinin vivoinsightkidney celllipooligosaccharidelipopolysaccharide-binding proteinmutantneutrophilnovelnovel strategiespathogenpolyacrylamide gelspolyhistidineprotein Eprotein protein interactionpublic health relevancereceptorresponsetoll-like receptor 4
项目摘要
DESCRIPTION (provided by applicant): Host defense against many invading Gram-negative bacteria (GNB) depends upon innate immune recognition of endotoxin (E), unique, abundant and generally conserved glycolipids of GNB. Optimal TLR4- dependent responses are exquisitely sensitive and robust, but also self-limited. How this is normally achieved and why regulation of TLR4 activation may go awry under various patho-physiological conditions is incompletely known. The most potent inflammatory responses to E require certain canonical structural features of E and ordered protein-E and protein-protein interactions involving the LPS-binding protein (LBP), CD14, MD-2, and Toll-like receptor (TLR) 4. MD-2 plays an essential role in regulation of TLR4 activation by E, by bridging recognition of E, normally initiated by LBP and CD14, to receptor activation or antagonism. Our identification and characterization of monomeric E.MD-2 complexes as potent TLR4 agonists or antagonists, depending on E and/or MD-2 structure, have clearly demonstrated that it is the properties of the E.MD-2 complex, not E alone, that specifies TLR4 activation or receptor occupancy without activation. The unique structural and functional properties of these complexes suggest novel approaches to investigate how endotoxin induces TLR4 activation, how differences in E structure can dictate differences in TLR4 responsiveness, and how these new mechanistic insights may be translated to the development of novel TLR4-directed immunomodulators. Growing evidence of a broader array of molecules that can act as TLR4 agonists or antagonists, including host and/or diet-derived lipids, suggest many other circumstances in which the regulation or dysregulation of MD-2/TLR4 function could be pivotal in host physiology and patho-physiology. We will make use of novel synthetic, biochemical, structural biological, and functional approaches (e.g., metabolically labeled native and synthetic E and lipid A variants, recombinant wild-type and mutant human E-binding proteins and TLR4 ectodomain, monoclonal antibodies, models of airway infection and inflammation) to: 1) Further define the structural properties of ligands that promote binding to MD-2 and the action of ligand.MD-2 complexes as TLR4 agonists or antagonists; 2) Define more specifically the structural properties of E.MD-2 complexes that activate TLR4; and 3) Better define in vivo actions in the murine airway of wt and variant E(lipdA).Md-2.
描述(由申请人提供):宿主对许多入侵的革兰氏阴性菌(GNB)的防御依赖于内毒素(E)的先天免疫识别,内毒素(E)是GNB独特、丰富且普遍保守的糖脂。最佳的 TLR4 依赖性反应非常敏感且稳健,但也是自限性的。通常如何实现这一点以及为什么 TLR4 激活的调节在各种病理生理条件下可能会出错尚不完全清楚。对 E 最有效的炎症反应需要 E 的某些典型结构特征以及涉及 LPS 结合蛋白 (LBP)、CD14、MD-2 和 Toll 样受体 (TLR) 4 的有序蛋白质-E 和蛋白质-蛋白质相互作用。 MD-2 通过桥接通常由 LBP 和 CD14 启动的 E 识别与受体激活或拮抗,在 E 调节 TLR4 激活中发挥重要作用。我们根据 E 和/或 MD-2 结构对单体 E.MD-2 复合物作为有效 TLR4 激动剂或拮抗剂的鉴定和表征,清楚地证明了这是 E.MD-2 复合物的特性,而不是 E 单独的特性,指定 TLR4 激活或受体占用而不激活。这些复合物独特的结构和功能特性提出了新的方法来研究内毒素如何诱导 TLR4 激活、E 结构的差异如何决定 TLR4 反应性的差异,以及这些新的机制见解如何转化为新型 TLR4 导向的免疫调节剂的开发。越来越多的证据表明,更广泛的分子可以充当 TLR4 激动剂或拮抗剂,包括宿主和/或饮食来源的脂质,这表明在许多其他情况下,MD-2/TLR4 功能的调节或失调可能在宿主生理学中发挥关键作用和病理生理学。我们将利用新的合成、生化、结构生物学和功能方法(例如,代谢标记的天然和合成的 E 和脂质 A 变体、重组野生型和突变型人 E 结合蛋白和 TLR4 胞外域、单克隆抗体、气道感染和炎症)以:1)进一步定义促进与MD-2结合的配体的结构特性以及配体的作用。MD-2复合物作为TLR4激动剂或拮抗剂; 2) 更具体地定义激活TLR4的E.MD-2复合物的结构特性; 3)更好地定义wt和变体E(lipdA).Md-2在小鼠气道中的体内作用。
项目成果
期刊论文数量(27)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The cationic amphiphile 3,4-bis(tetradecyloxy)benzylamine inhibits LPS signaling by competing with endotoxin for CD14 binding.
- DOI:10.1016/j.bcp.2010.06.019
- 发表时间:2010-12-15
- 期刊:
- 影响因子:5.8
- 作者:Piazza M;Calabrese V;Baruffa C;Gioannini T;Weiss J;Peri F
- 通讯作者:Peri F
Evidence of a specific interaction between new synthetic antisepsis agents and CD14.
- DOI:10.1021/bi901601b
- 发表时间:2009-12-29
- 期刊:
- 影响因子:2.9
- 作者:Piazza, Matteo;Yu, Liping;Teghanemt, Athmane;Gioannini, Theresa;Weiss, Jerrold;Peri, Francesco
- 通讯作者:Peri, Francesco
Hemin and a metabolic derivative coprohemin modulate the TLR4 pathway differently through different molecular targets.
- DOI:10.1177/1753425910369020
- 发表时间:2011-02
- 期刊:
- 影响因子:3.2
- 作者:Piazza M;Damore G;Costa B;Gioannini TL;Weiss JP;Peri F
- 通讯作者:Peri F
Expression of functional D299G.T399I polymorphic variant of TLR4 depends more on coexpression of MD-2 than does wild-type TLR4.
- DOI:10.4049/jimmunol.0903142
- 发表时间:2010-04-15
- 期刊:
- 影响因子:0
- 作者:Prohinar P;Rallabhandi P;Weiss JP;Gioannini TL
- 通讯作者:Gioannini TL
Endotoxin{middle dot}albumin complexes transfer endotoxin monomers to MD-2 resulting in activation of TLR4.
- DOI:10.1177/1753425911422723
- 发表时间:2012-06
- 期刊:
- 影响因子:3.2
- 作者:Esparza GA;Teghanemt A;Zhang D;Gioannini TL;Weiss JP
- 通讯作者:Weiss JP
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JERROLD P WEISS其他文献
JERROLD P WEISS的其他文献
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{{ truncateString('JERROLD P WEISS', 18)}}的其他基金
MOBILIZATION AND DELIVERY OF LIPOOLIGOSACCHARIDES TO HOST TARGETS
脂寡糖的动员和递送至宿主靶标
- 批准号:
6653280 - 财政年份:2002
- 资助金额:
$ 33.24万 - 项目类别:
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