Mechanisms of Airway Epithelial Barrier Dysfunction by Respiratory Syncytial Virus and Environmental Stimuli
呼吸道合胞病毒和环境刺激导致气道上皮屏障功能障碍的机制
基本信息
- 批准号:10657436
- 负责人:
- 金额:$ 43.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalActin-Binding ProteinActinsAcuteAdultAdverse effectsAffectAgeAir PollutionAirway DiseaseAntioxidantsApicalArtificial nanoparticlesAttenuatedCell SeparationChildChildhoodComplexCyclic AMPCytoskeletonDataDepositionDistalDown-RegulationEMS1 geneEnvironmental PollutantsEnvironmental PollutionEpidemiologyEpithelial CellsEpitheliumEventExposure toFilamentFree RadicalsFunctional disorderGenerationsHospitalizationHost DefenseHouseholdHumanHuman Cell LineIn VitroInfantInflammationInjuryKnockout MiceLinkLower Respiratory Tract InfectionLungMeasurementMediatingMethodsMicrofilamentsMissionModelingMolecularMonomeric GTP-Binding ProteinsMorbidity - disease rateMusNanotechnologyOrganoidsOutcomeOxidative StressOxidative Stress InductionParticle SizeParticulate MatterPathologyPathway interactionsPersonal SatisfactionPolymersProductionReportingResearchRespiration DisordersRespiratory Syncytial Virus InfectionsRespiratory syncytial virusRiskRodentRoleSeveritiesSignaling MoleculeSourceStandardizationStimulusStructureTestingTherapeutic InterventionUnited States National Institutes of HealthVascular EndotheliumVascular PermeabilitiesVirusVirus DiseasesVirus Replicationairway epitheliumairway hyperresponsivenessbronchial epitheliumclinically relevantcommercial applicationconsumer productdepolymerizationdesignepithelial injurygain of functionhigh riskin vivoin vivo Modelinjured airwayinnovationinsightintestinal epitheliumloss of functionmortalitymouse modelnanomaterialsnanoparticlenew therapeutic targetnovelparticlepolymerizationtitanium dioxideyoung adult
项目摘要
ABSTRACT
Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections (ALRI) in children
and high-risk adults worldwide. Our data demonstrate that RSV infection results in a ‘leaky airway’ by disrupting
epithelial apical junctional complexes (AJC), which regulate the airway epithelial barrier. We show that RSV-
mediated disruption of AJC is accompanied by disassembly of the perijunctional actin cytoskeleton, and
downregulation of cortactin - a key actin-binding protein. Cortactin deficiency has been previously implicated in
destabilizing the vascular endothelial and intestinal epithelial barrier. However the causal link between RSV-
induced leaky barrier, actin cytoskeletal rearrangements and cortactin deficiency have not been established. In
addition, epidemiological reports suggest a strong association between exposure to ambient particulate matter
(PM) and increased risk of ALRI. Nanoparticles (NPs) are extremely small PM, with the greater ability to become
deposited in distal airways and evade host defenses compared to smaller particles. Our preliminary data
demonstrate that pre-exposure of bronchial epithelial cells to NP not only enhances RSV-induced AJC
disassembly and actin cytoskeleton disruption, but augments viral infection. Based on our novel observations,
we formulated the central hypotheses that a) RSV induces disruption of the airway epithelial barrier by triggering
depolymerization of the perijunctional actin cytoskeleton, and by downregulating cortactin; and b) that disruption
of the epithelial barrier by nanoparticles worsens RSV-induced airway epithelium injury. We will test our
hypotheses through the following Specific Aims: Aim 1: To determine the role of cortactin-dependent actin
filament dynamics in RSV-induced airway epithelial barrier dysfunction. Using human bronchial epithelial cells
isolated from pediatric donors, and a mouse model of cortactin null mice, we will investigate (i) RSV effect on
actin cytoskeletal dynamics, (ii) the functional role of cortactin on actin dynamics and AJC structure, and (iii) the
functional roles of Rap-1. We will also use a 3-D human lung organoids model detailing the effects of AJC
disruption upon RSV infection, which offers an innovative platform to study complex host-environmental
interactions. Aim 2: To determine if nanoparticles enhance RSV-induced disruption of the airway epithelial
barrier. Using in vitro and in vivo models, we will (i) characterize the effects of particle size on barrier integrity,
(ii) study role of oxidative stress on AJC function, and (iii) define the effects of exposure to NP on AJC
dysfunction. The proposed research is significant and relevant to the NIH’s mission as we aim to explore the
clinically relevant consequences of RSV infection on airway barrier integrity, and how exposure to environmental
pollutants worsens RSV infection. Our approach is innovative because it will provide new mechanistic insight in
to the roles of RSV in AJC disassembly, as well as novel insight in to the effects of NPs in enhancing RSV-
induced AJC disruption. The identified pathways will provide new targets for therapeutic intervention and the
potential for positively impacting the management of RSV disease.
摘要
项目成果
期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Airway tight junctions as targets of viral infections.
- DOI:10.1080/21688370.2021.1883965
- 发表时间:2021-04-03
- 期刊:
- 影响因子:3.1
- 作者:Linfield DT;Raduka A;Aghapour M;Rezaee F
- 通讯作者:Rezaee F
Role of air pollutants in airway epithelial barrier dysfunction in asthma and COPD.
- DOI:10.1183/16000617.0112-2021
- 发表时间:2022-03-31
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Effects of Vertical Transmission of Respiratory Viruses to the Offspring.
- DOI:10.3389/fimmu.2022.853009
- 发表时间:2022
- 期刊:
- 影响因子:7.3
- 作者:Manti S;Leonardi S;Rezaee F;Harford TJ;Perez MK;Piedimonte G
- 通讯作者:Piedimonte G
Airway Epithelial Cell Junctions as Targets for Pathogens and Antimicrobial Therapy.
- DOI:10.3390/pharmaceutics14122619
- 发表时间:2022-11-27
- 期刊:
- 影响因子:5.4
- 作者:Gao N;Rezaee F
- 通讯作者:Rezaee F
Pediatric pneumothorax: Case studies and review of current literature.
- DOI:10.1016/j.rmcr.2021.101548
- 发表时间:2021
- 期刊:
- 影响因子:1.1
- 作者:Yousuf S;Cardenas S;Rezaee F
- 通讯作者:Rezaee F
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{{ truncateString('Fariba Rezaee', 18)}}的其他基金
Mechanisms of Airway Epithelial Barrier Dysfunction by Respiratory Syncytial Virus and Environmental Stimuli
呼吸道合胞病毒和环境刺激导致气道上皮屏障功能障碍的机制
- 批准号:
10443817 - 财政年份:2019
- 资助金额:
$ 43.99万 - 项目类别:
Mechanisms of Airway Epithelial Barrier Dysfunction by Respiratory Syncytial Virus and Environmental Stimuli
呼吸道合胞病毒和环境刺激导致气道上皮屏障功能障碍的机制
- 批准号:
10208949 - 财政年份:2019
- 资助金额:
$ 43.99万 - 项目类别:
Airway Epithelial Barrier Dysfunction In Response to Respiratory Syncytial Virus
呼吸道合胞病毒引起的气道上皮屏障功能障碍
- 批准号:
8990806 - 财政年份:2015
- 资助金额:
$ 43.99万 - 项目类别:
Airway Epithelial Barrier Dysfunction In Response to Respiratory Syncytial Virus
呼吸道合胞病毒引起的气道上皮屏障功能障碍
- 批准号:
9190362 - 财政年份:2015
- 资助金额:
$ 43.99万 - 项目类别:
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