Nox family NADPH oxidases: roles in innate immunity and inflammatory disease
Nox 家族 NADPH 氧化酶:在先天免疫和炎症性疾病中的作用
基本信息
- 批准号:8336081
- 负责人:
- 金额:$ 122.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:4-ethoxymethylene-2-phenyl-2-oxazoline-5-oneAffectAnabolismAnimal ModelAntioxidantsApicalApoptosisAsthmaAutocrine CommunicationBacterial InfectionsBiochemicalBiological AssayBlood VesselsBrainCaspaseCell AgingCell Culture TechniquesCell Differentiation processCellsChronicChronic Granulomatous DiseaseCretinismCystic FibrosisDTR geneDefectDiseaseDouble-Stranded RNAEnzyme-Linked Immunosorbent AssayEpidermal Growth Factor ReceptorEpithelialEpithelial CellsExhibitsExocrine GlandsExtracellular MatrixFamilyFlagellinGastrointestinal tract structureGene ExpressionGene Expression ProfilingGenesGenetic PolymorphismGrowth FactorHepatitis CHormonesHost DefenseHydrogen PeroxideImmuneImmune responseImmunocompromised HostIndividualInfectionInflammatoryInflammatory Bowel DiseasesInflammatory ResponseInterleukin-6InvestigationIsoenzymesKidneyLigandsLinkLipopolysaccharidesLiverLungMediatingMicrobeMicrobial BiofilmsModelingMolecularMouse StrainsMucinsMucous MembraneMusMutationNADPH OxidaseNatural ImmunityNox enzymeOxidasesOxidation-ReductionOxidative StressOxygenParacrine CommunicationPathogenesisPathway interactionsPatientsPatternPeroxidasesPhagocytesPhenotypePoly I-CPredispositionProcessProductionPseudomonasPseudomonas aeruginosaPyocyanineReactive Oxygen SpeciesRoleSalivary GlandsSignal PathwaySignal TransductionSingle Nucleotide PolymorphismSmall Interfering RNAStimulusSuperoxidesSurfaceSystemTLR3 geneTechnologyThyroid GlandTissuesToxinTransforming Growth Factor alphaTumor Necrosis Factor ReceptorTumor Necrosis Factor-alphaType III Secretion System PathwayViralVirulence FactorsVirus Diseasesairway epitheliumantimicrobialbasecellular targetingcystic fibrosis patientscytokinedefense responsehuman TNF proteininhibitor/antagonistinsightinterestkillingslactoperoxidasemicrobialmicrobicidemouse modelneutralizing antibodynovelpathogenprogramsreceptorreconstitutionresponsetissue/cell culture
项目摘要
This program explores innate anti-microbial defense and inflammatory mechanisms involving deliberate reactive oxygen species (ROS) production by the host. Circulating phagocytes generate high levels of ROS that serve as important microbicidal agents in response to infectious or inflammatory stimuli, which is attributed to NADPH oxidase activation. Patients with chronic granulomatous disease (CGD) suffer from NADPH oxidase (Nox2- or phox-based) deficiencies, resulting in enhanced susceptibility to microbial infections and aberrant inflammatory responses. Our current focus investigates cellular mechanisms regulating related Nox family NADPH oxidases expressed in non-phagocytic cells (Nox1, Nox4, Duox1, Duox2), notably on mucosal surfaces (lung and gastrointestinal tract), the liver, kidney, thyroid and salivary glands, brain, and vascular tissues. ROS produced by these oxidases provide redox signals that affect gene expression patterns during responses to infection, oxygen sensing, growth factors, hormones, cytokines, cell differentiation, cellular senescence, programmed cell death (apoptosis). Several non-phagocytic Nox enzymes also serve in host defense and inflammatory processes, as they are expressed predominately on apical surfaces of epithelial cells and are induced or activated by cytokines or by recognition of pathogen-associated molecular patterns. Recently, we found that mature ciliated airway epithelial cells produce sufficient Duox-derived hydrogen peroxide to support lactoperoxidase-mediated killing of several airway pathogens, and that freshly grown Pseudomonas aeruginosa elicits airway epithelial Duox activation in response to multiple microbial factors (lipopolysaccharide, flagellin and the type III secretion system). In contrast, overgrown Pseudomonas secretes a microbial toxin (pyocyanin) that competitively inhibits Duox activity as it produces intracellular superoxide and imposes oxidative stress on host cells. The latter process in this 'redox warfare' between host and microbe represents a counter-offensive adaptation of Pseudomonas during the establishment of biofilms.
In 2011, we have studied in detail the importance of the redox-active Pseudomonas aeruginosa virulence factor, pyocyanin, in the pathogenesis of chronic Pseudomonas airway infections. This factor is produced in response to quorum signals when Pseudomonas is overgrown in biofilms of chronically infected lungs of immunocompromised individuals (i.e., cystic fibrosis patients). We showed the effects of (purified) pyocyanin-mediated oxidative stress imposed on isolated airway epithelial cells recapitulate many of the phenotypic features of advanced cystic fibrosis disease, including mucin hypersecretion (mucin5a and mucin2) and release of pro-inflammatory cytokines and inflammatory cell-stimulating and chemotactic agents. These responses were detected initially by microarray-based gene expression profiling, which identified some 286 genes upregulated by pyocyanin. The importance of many of the induced genes was confirmed by ELISA assays of secreted cytokines and putative EGF receptor ligands. Biochemical, pharmacological, and antibody-neutralizing approaches were then used to establish a mechanistic model for pyocyanin-induced mucin hypersecretion in which several secreted epidermal growth factor receptor (EGFR) ligands (IL-beta, IL-6, TGF-alpha, TNF-alpha, HB-EGF) were shown to act through autocrine or paracrine signaling pathways to promote mucin secretion. These findings suggest potential utility of therapies aimed at the effects of this toxin for treating advance cystic fibrosis disease, and they provide insights into recent findings showing that chronic pyocyanin administration into mouse airways produces a cystic fibrosis-like phenotype.
In other collaborative studies, we examined innate immune responses of airway epithelial cells to polyinosinic-polycytidylic acid (poly I:C), as a mimic of viral double-stranded RNA signaling through TLR3 pathways. Poly I:C was shown to induce shedding of a soluble TNF receptor ectodomain (sTNFR1), which could down-regulating cellular responses to TNF-alpha. We demonstrated that receptor shedding requires two pathways: one involving Duox2-mediated hydrogen peroxide release and the other involving caspase-mediated apoptosis. Poly I:C triggered hydrogen peroxide production and sTNFR1 shedding from airway cells, which was suppressed by siRNA-mediated Duox2 knockdown, oxidase inhibitors, or antioxidants. These findings reveal novel mechanisms by which innate immune and inflammatory responses of airway epithelium to viral infection can be modulated.
Our advances in Duox reconstitution technology have identified several Duox single nucleotide polymorphisms (SNPs) or mutations that alter oxidase function or cellular targeting, which may relate to congenital hypothyroidism or altered susceptibilities to airway infectious or inflammatory disease (cystic fibrosis, asthma, bacterial or viral infection). Other Duox polymorphisms identified between mouse strains that exhibit altered susceptibilities to inflammatory bowel disease are being investigated for alterations in oxidase function.
该计划探讨了先天的抗微生物防御和炎症机制,涉及宿主的故意活性氧(ROS)生产。循环吞噬细胞会产生高水平的ROS,这些ROS响应于传染性或炎症刺激,这是NADPH氧化酶的激活。患有慢性肉芽肿性疾病(CGD)患者患有NADPH氧化酶(基于NOX2或PHOX)缺乏症,导致对微生物感染和异常炎症反应的敏感性增强。我们目前的重点研究了调节在非噬细胞细胞(NOX1,NOX4,DUOX1,DUOX2)中表达的相关NOX家族NADPH氧化酶的细胞机制,特别是在粘膜表面(肺和胃肠道),肝脏,肝脏,肾脏,甲状腺和唾液腺,脑脑,脑,脑,脑,脑脑和流动性组织。这些氧化酶产生的ROS提供了氧化还原信号,该信号在对感染,氧气感应,生长因子,激素,细胞因子,细胞分化,细胞衰老,程序性细胞死亡(凋亡)(凋亡)的反应过程中影响基因表达模式。 几种非变形细胞NOX酶也用于宿主防御和炎症过程,因为它们主要在上皮细胞的顶端表面表达,并被细胞因子或通过病原体相关的分子模式诱导或激活。最近,我们发现,成熟的纤毛气道上皮细胞产生足够的DUOX衍生的过氧化氢,以支持乳酸氧化酶介导的几种气道病原体的杀戮,并且新鲜生长的铜绿假单胞菌激发了气道气道呼吸道激活,以响应多种微生物因子(lipopolysacy and frangirian conyrion和FragiriN)。相反,杂草质假单胞菌分泌一种微生物毒素(pyocyanin),该毒素会抑制DUOX活性,因为它会产生细胞内的超氧化物,并对宿主细胞施加氧化应激。 在宿主和微生物之间的“氧化还原战”中的后一个过程代表了生物膜建立期间假单胞菌的反攻适应。
2011年,我们详细研究了氧化还原活性假单胞菌毒力因子Pyocyanin在慢性假单胞菌气道感染的发病机理中的重要性。当假单胞菌在慢性感染的免疫功能低下个体的肺(即囊性纤维化患者)的生物膜中过长时,该因子是根据法定信号响应的。我们展示了(纯化的)增氨酸介导的氧化应激对孤立气道上皮细胞施加的氧化应激,概括了晚期囊性纤维化疾病的许多表型特征,包括粘蛋白过度分泌(Mucin5a和Mucin2)(Mucin5a和Mucin2),以及促炎细胞因子和炎性细胞的释放和炎症细胞症状和化学症状。这些反应最初是通过基于微阵列的基因表达分析检测到的,该基因表达分析鉴定出大约286个由增值苷上调的基因。 ELISA分泌的细胞因子和推定的EGF受体配体证实了许多诱导基因的重要性。 Biochemical, pharmacological, and antibody-neutralizing approaches were then used to establish a mechanistic model for pyocyanin-induced mucin hypersecretion in which several secreted epidermal growth factor receptor (EGFR) ligands (IL-beta, IL-6, TGF-alpha, TNF-alpha, HB-EGF) were shown to act through autocrine or paracrine signaling促进粘蛋白分泌的途径。这些发现表明,针对这种毒素对治疗囊性纤维化疾病的影响的疗法的潜在效用,它们对最近发现的见解表明,慢性增生酸在小鼠气道中的施用会产生类似囊性纤维化的表型。
在其他协作研究中,我们研究了气道上皮细胞对聚激素 - 多胞辛酸(Poly I:C)的先天免疫反应,作为通过TLR3途径的病毒双链RNA信号传导的模仿。 Poly I:C被证明会诱导可溶性TNF受体外域(STNFR1)的脱落,该域可能会下调对TNF-α的细胞反应。我们证明受体脱落需要两种途径:一种涉及DUOX2介导的过氧化氢释放,另一种涉及caspase介导的细胞凋亡。 Poly I:C触发过氧化氢的产生和STNFR1从气道细胞中脱落,这被siRNA介导的DUOX2敲低,氧化酶抑制剂或抗氧化剂抑制。这些发现揭示了新的机制,可以调节气道上皮对病毒感染的先天免疫和炎症反应。
我们在DUOX重建技术方面的进步已经确定了几种DUOX单核苷酸多态性(SNP)或改变氧化酶功能或细胞靶向的突变,这可能与先天性甲状腺功能低下或对气道感染性或炎症性疾病(细胞纤维化,细菌,细菌感染或病毒感染)的易感性有关。 在小鼠菌株之间鉴定出的其他DUOX多态性,正在研究炎性肠病的敏感性改变,以改变氧化酶功能的改变。
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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THOMAS LETO其他文献
THOMAS LETO的其他文献
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{{ truncateString('THOMAS LETO', 18)}}的其他基金
Role of Reactive Oxygen Species in Lymphocyte Development and Function
活性氧在淋巴细胞发育和功能中的作用
- 批准号:
10272142 - 财政年份:
- 资助金额:
$ 122.08万 - 项目类别:
NOX family NADPH oxidases: roles in innate immunity and inflammatory disease
NOX 家族 NADPH 氧化酶:在先天免疫和炎症性疾病中的作用
- 批准号:
10692034 - 财政年份:
- 资助金额:
$ 122.08万 - 项目类别:
Role of Reactive Oxygen Species in Lymphocyte Development and Function
活性氧在淋巴细胞发育和功能中的作用
- 批准号:
8157049 - 财政年份:
- 资助金额:
$ 122.08万 - 项目类别:
Nox family NADPH oxidases: roles in innate immunity and inflammatory disease
Nox 家族 NADPH 氧化酶:在先天免疫和炎症性疾病中的作用
- 批准号:
8156865 - 财政年份:
- 资助金额:
$ 122.08万 - 项目类别:
Role of Reactive Oxygen Species in Lymphocyte Development and Function
活性氧在淋巴细胞发育和功能中的作用
- 批准号:
8336273 - 财政年份:
- 资助金额:
$ 122.08万 - 项目类别:
Role of Reactive Oxygen Species in Lymphocyte Development and Function
活性氧在淋巴细胞发育和功能中的作用
- 批准号:
10927826 - 财政年份:
- 资助金额:
$ 122.08万 - 项目类别:
Role of Reactive Oxygen Species in Lymphocyte Development and Function
活性氧在淋巴细胞发育和功能中的作用
- 批准号:
10014150 - 财政年份:
- 资助金额:
$ 122.08万 - 项目类别:
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Structure/Function Analysis of Phagocyte Proteins
吞噬细胞蛋白的结构/功能分析
- 批准号:
7256400 - 财政年份:1991
- 资助金额:
$ 122.08万 - 项目类别:
Structure/Function Analysis of Phagocyte Proteins
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