Asthma susceptibility due to environmental programing of innate immunity in utero
由于子宫内先天免疫的环境编程而导致哮喘易感性
基本信息
- 批准号:8818875
- 负责人:
- 金额:$ 39.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-01-01 至 2019-11-30
- 项目状态:已结题
- 来源:
- 关键词:5 year oldAddressAdoptive TransferAdultAge-YearsAir PollutionAllergensAntibodiesAntiviral ResponseAromatic Polycyclic HydrocarbonsAryl Hydrocarbon ReceptorAsthmaBenzo(a)pyreneBiological PreservationCellsChildDNA AdductsDataDevelopmentDiesel ExhaustDiseaseEnvironmental ExposureEpidemiologic StudiesEpidemiologyExposure toFemaleFosteringFrequenciesGene ExpressionGenerationsGeneticGenetic TranscriptionGenotypeGoalsHumanImmunityImmunizationIn VitroIncidenceInflammationInterleukin-13Interleukin-17Interleukin-5KnowledgeLifeLinkLungMaternal ExposureMaternal-Fetal TransmissionMeasuresMediatingMessenger RNAModelingMolecularMusMutationNK Cell ActivationNatural ImmunityNatural Killer CellsOrganOvalbuminPerinatal ExposurePhenotypePredispositionProcessProductionProliferatingProteinsRegimenReportingRiskRisk FactorsRoleSurrogate MothersSystemT-LymphocyteTranscriptUp-RegulationWheezingadaptive immunityaryl hydrocarbon receptor ligandasthma preventionasthmaticbasecytokinecytotoxicdisorder controlearly childhoodearly onsetin uteroindexingmeetingsmouse modeloffspringparticleparticle exposureperipheral bloodpostnatalpregnantprenatalprenatal environmental exposureprenatal exposurepreventprogramspublic health relevancepupresearch studyresponsetumor
项目摘要
DESCRIPTION (provided by applicant): Prenatal environmental exposures are increasingly recognized as important risk factors for asthma. Critical exposures include urban air pollution and its component - diesel exhaust. The mechanisms are poorly characterized. This project seeks to address this gap in knowledge. To build a framework for mechanistic studies we have developed a mouse model. In this model, repeated exposure of pregnant mice to diesel exhaust particles (DEP) renders their offspring hypersensitive to the postnatal allergen - ovalbumin (OVA). These offspring develop asthma when subjected to suboptimal OVA sensitization and challenge. In contrast, pups born to unexposed dams do not develop asthma upon suboptimal OVA exposure. Our preliminary data indicate that asthma in this model is mediated by NK cells that produce IL-5, IL-13 and IL-17. Depletion of these cells using specific antibodies prevents asthma. We also show that IL-5/IL-13/IL-17+ NK cells are increased in human asthma. In addition to IL-5, IL-13 and IL-17 production, the pathogenic mouse NK cells are characterized by increased expression of the aryl hydrocarbon receptor (AhR) signature transcripts (AhRR, Cyp1a1 and Cyp1b1). AhR is a transcriptional factor that is known to respond to organic compounds of DEP, namely, polycyclic aromatic hydrocarbons (PAH). AhR is also known to regulate the IL-17 gene transcription. Some reports suggest the positive role of AhR in IL-5 and IL-13 production. Thus, AhR provides a molecular link between maternal exposure to DEP and cytokine production in offspring NK cells. Based on these data, our overarching hypothesis is that in utero exposure to diesel exhaust promotes asthma susceptibility through AhR-dependent priming of NK cells. We propose following specific aims: 1) Examine the importance of NK cells in asthma susceptibility induced via prenatal exposure to DEP; 2) Study the role of the aryl hydrocarbon receptor in NK cell activation and maternal-fetal transmission of asthma risk; 3) Examine the persistence of the pathogenic DEP effect through the life of first and subsequent generations; 4) Examine the relevance of IL- 5/IL-13/IL-17+ NK cells and AhR/AhRR/Cyp1b1+ NK cells in human asthma. To meet these goals we will use NK cell-deficient mice, mice without adaptive immunity and mice with NK cell-specific deletion of AhR. We will also perform transfers of NK cells from prenatally exposed offspring to unexposed mice. To study preservation of asthma susceptibility throughout the offspring life we will use cross-fostering and delayed allergen exposure approaches. To study transgenerational effects of DEP exposure, we will examine asthma susceptibility in F2 and F3 offspring. To determine human relevance we will measure IL-5/IL-13/IL-17+ NK cells and AhR/AhRR/Cyp1b1+ NK cells in young children and adults with asthma. We will correlate NK cell results with amounts of PAH-DNA adducts (a measure of environmental exposure). Using an in vitro culture system we will determine whether DEP can skew non-polarized NK cells from non-allergic non-asthmatic donors into IL-5/IL- 13/IL-17-producing cells. We will then study the role of AhR in this process using a knockdown approach.
描述(由申请人提供):产前环境暴露越来越被认为是哮喘的重要危险因素。关键的暴露包括城市空气污染及其组件 - 柴油排气。这些机制的特征很差。该项目旨在解决知识的差距。为了建立机械研究的框架,我们开发了鼠标模型。在此模型中,怀孕小鼠反复暴露于柴油排气颗粒(DEP)使其后代对产后过敏原-Ovalbumin(OVA)过敏。当受到次优的OVA敏感性和挑战时,这些后代会发展哮喘。相比之下,未暴露的大坝出生的幼崽不会在次优的OVA暴露时出现哮喘。我们的初步数据表明,该模型中的哮喘是由产生IL-5,IL-13和IL-17的NK细胞介导的。使用特定抗体对这些细胞的耗竭可预防哮喘。我们还表明,人类哮喘中IL-5/IL-13/IL-17+ NK细胞增加。除IL-5,IL-13和IL-17的产生外,病原小鼠NK细胞的特征是芳基烃受体(AHR)特征转录本的表达增加(AHRR,CYP1A1和CYP1B1)。 AHR是一种转录因子,已知可以对DEP的有机化合物响应,即多环芳烃(PAH)。还已知AHR调节IL-17基因转录。一些报告表明AHR在IL-5和IL-13产生中的积极作用。因此,AHR在后代NK细胞中的母体暴露于DEP和细胞因子的产生之间提供了分子联系。基于这些数据,我们的总体假设是,在子宫内暴露于柴油机上,通过NK细胞的AHR依赖性启动来促进哮喘的敏感性。我们提出以下特定目的:1)检查通过产前暴露于DEP引起的NK细胞在哮喘易感性中的重要性; 2)研究芳基碳氢化合物受体在NK细胞激活和哮喘风险的母亲传播中的作用; 3)检查病原DEP效应的持续性,通过第一和后代的生命; 4)检查人类哮喘中IL-5/IL-13/IL-13/IL-17+ NK细胞和AHR/AHRR/CYP1B1+ NK细胞的相关性。为了实现这些目标,我们将使用NK细胞缺陷型小鼠,无适应性免疫的小鼠,而NK细胞特异性删除AHR的小鼠。我们还将从产前暴露的后代到未暴露的小鼠进行NK细胞的转移。为了研究整个后代寿命的哮喘敏感性,我们将使用交叉促进和延迟的过敏原暴露方法。为了研究DEP暴露的转世代作用,我们将检查F2和F3后代的哮喘敏感性。为了确定人类相关性,我们将测量患有哮喘的幼儿和成人的IL-5/IL-13/IL-17+ NK细胞和AHR/AHRR/CYP1B1+ NK细胞。我们将将NK细胞结果与PAH-DNA加合物(环境暴露的量度)相关联。使用体外培养系统,我们将确定DEP是否可以将非偏振的NK细胞偏向于IL-5/IL-13/IL-17产生的细胞中的非非过敏性供体的非偏振细胞。然后,我们将使用敲低方法研究AHR在此过程中的作用。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Magdalena Maria Gorska其他文献
Magdalena Maria Gorska的其他文献
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{{ truncateString('Magdalena Maria Gorska', 18)}}的其他基金
Maternal programming of the stem cell-basophil axis for asthma
哮喘干细胞-嗜碱性粒细胞轴的母体编程
- 批准号:
10219912 - 财政年份:2020
- 资助金额:
$ 39.63万 - 项目类别:
Maternal programming of the stem cell-basophil axis for asthma
哮喘干细胞-嗜碱性粒细胞轴的母体编程
- 批准号:
9886147 - 财政年份:2020
- 资助金额:
$ 39.63万 - 项目类别:
Maternal programming of the stem cell-basophil axis for asthma
哮喘干细胞-嗜碱性粒细胞轴的母体编程
- 批准号:
10441348 - 财政年份:2020
- 资助金额:
$ 39.63万 - 项目类别:
Asthma susceptibility due to environmental programming of innate immunity in utero
由于子宫内先天免疫的环境编程而导致哮喘易感性
- 批准号:
10318567 - 财政年份:2015
- 资助金额:
$ 39.63万 - 项目类别:
Asthma susceptibility due to environmental programming of innate immunity in utero
由于子宫内先天免疫的环境编程而导致哮喘易感性
- 批准号:
10532221 - 财政年份:2015
- 资助金额:
$ 39.63万 - 项目类别:
Asthma susceptibility due to environmental programing of innate immunity in utero
由于子宫内先天免疫的环境编程而导致哮喘易感性
- 批准号:
8991512 - 财政年份:2015
- 资助金额:
$ 39.63万 - 项目类别:
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