Role of hepatic IkBb-mediated sustained NFkB activation in neonatal lung injury and abnormal development
Role of hepatic IkBb-mediated sustained NFkB activation in neonatal lung injury and abnormal development
批准号:
9258241
负责人:
Clyde Jason Wright
金额:
$37.54万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-01-01 至 2021-11-30
关键词:
AdultAffectAnimalsAnti-Inflammatory AgentsAnti-inflammatoryAttenuatedBindingBiological MarkersBronchopulmonary DysplasiaCell NucleusCellsChronicDataDevelopmentDimerizationEndotoxemiaEquilibriumFamilyFoundationsGene ExpressionGene TargetingGeneticHepaticI Kappa B-AlphaImmune signalingImmunologicsImpairmentIncidenceInfantInflammationInflammation MediatorsInflammatoryInflammatory ResponseInjuryInnate Immune ResponseInnate Immune SystemKineticsLaboratoriesLifeLinkLipidsLiverLungMediatingMolecularMolecular ProfilingMorbidity - disease rateMusNatural ImmunityNeonatalNuclearNuclear TranslocationOrganOutcomePathogenesisPatternPerinatalPharmacologyPhosphorylationPhysiologicalPlasmidsPlayPremature BirthPremature InfantPrevention approachProtein IsoformsProteinsPulmonary InflammationRiskRoleSignal TransductionSmall Interfering RNAStimulusStressTestingTherapeuticTranscription Repressor/CorepressorWorkbasedimerin vivolung developmentlung injurymacrophagenanoparticleneonatal careneonatal lung injuryneonatepreventpulmonary functionresponsetranscription factortranscriptomeupstream kinase
中文摘要
项目摘要
支气管肺发育不良(BPD)是早产最常见的并发症,
肺部和神经发育不良。尽管有充分的证据表明
由于炎症和BPD的关系,目前没有安全有效的抗炎疗法来预防BPD,
available.新生儿先天免疫应答如何导致BPD的发病机制尚不清楚,
限制了治疗选择。我们的首要目标是确定连接这些细胞的分子机制。
新生儿先天性免疫反应和肺发育受损,导致
波士顿警局重要的是,我实验室最近的研究发现了一种发育调节的肝特异性
转录因子NFκB关键抑制蛋白的表达模式。由于NFκB在细胞凋亡中起核心作用,
在调节先天免疫方面,这些发现使我们提出了一个新的组织假说,
新生儿肝脏对肺损伤的天然免疫反应我们假设肝脏表达
NFκB抑制蛋白的IκB家族的特征导致持续的促炎性先天免疫
对全身炎症应激的反应,导致持续的肺部炎症、损伤和
发育受损。我们提出了三个具体的目标来测试这一假设,并确定免疫学
发育中的肺和肝之间的串扰。在目标1中,我们将测试细胞内的
IκBα/IκBβ决定了炎症应激诱导NFκB的大小、持续时间和选择性
转录组在目标2中,我们将测试是否有一个强大的和持续的促炎新生儿先天免疫,
反应导致肺损伤和异常发育。在目标3中,我们将测试是否抑制
炎症应激诱导的IκBβ介导的肝脏NF κ B B信号传导阻止了促炎基因的延长
表达并减轻新生儿肺损伤。我们的假设代表了一种范式的转变,
通过将持续的促炎新生儿先天免疫反应与BPD的预防联系起来,
通过肝脏IκBβ/NFκB信号通路介导肺损伤及随后的异常发展。这些研究
将为旨在药理学靶向IκBβ /NFκB信号传导的翻译工作提供基础
预防高危婴儿的BPD。
英文摘要
PROJECT SUMMARY
Bronchopulmonary dysplasia (BPD) is the most common morbidity complicating preterm birth and predicts
poor pulmonary and neurodevelopmental outcomes. Despite the well-documented association between
inflammation and BPD, no safe and effective anti-inflammatory therapies to prevent BPD are currently
available. How the neonatal innate immune response contributes to the pathogenesis of BPD is unknown,
limiting therapeutic options. Our overarching aim is to determine the molecular mechanisms linking the
neonatal innate immune response and impaired lung development that contributes to the pathogenesis of
BPD. Importantly, recent studies in my laboratory identified a developmentally-regulated, hepatic-specific
pattern of expression for key inhibitory proteins of the transcription factor NFκB. As NFκB plays a central role
in regulating innate immunity, these findings have led us to propose a new organizing hypothesis linking the
neonatal hepatic innate immune response to pulmonary injury. We hypothesize that the hepatic expression
profile of the IκB family of NFκB inhibitory proteins results in a sustained pro-inflammatory innate immune
response to systemic inflammatory stress that contributes to ongoing pulmonary inflammation, injury and
impaired development. We propose three specific aims to test this hypothesis and determine the immunologic
cross-talk between the developing lung and liver. In Aim 1, we will test whether the intracellular balance of
IκBα/IκBβ dictates the magnitude, duration and selectivity of the inflammatory-stress induced NFκB
transcriptome. In Aim 2, we will test whether a robust and sustained pro-inflammatory neonatal innate immune
response contributes to lung injury and abnormal development. In Aim 3, we will test whether inhibiting
inflammatory stress-induced, IκBβ-mediated hepatic NFB signaling prevents prolonged pro-inflammatory gene
expression and attenuates neonatal lung injury. Our hypothesis represents a paradigm shift in how we
approach the prevention of BPD by linking a sustained pro-inflammatory neonatal innate immune response
mediated by hepatic IκBβ/NFκB signaling to lung injury and subsequent abnormal development. These studies
will provide the foundation for translational work aimed at pharmacologically targeting IκBβ /NFκB signaling to
prevent BPD in at-risk infants.
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会议论文
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负责人:Clyde Jason Wright
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依托单位:
海外基金