Restoring mucociliary clearance apparatus to mitigate lung inflammation in the context of HIV and cigarette smoke
恢复粘膜纤毛清除装置以减轻艾滋病毒和香烟烟雾背景下的肺部炎症
基本信息
- 批准号:10547928
- 负责人:
- 金额:$ 14.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsAbbreviationsAccountingAffectAirAirway DiseaseAllergensAttenuatedBacteriaBacterial InfectionsBacterial PneumoniaBronchoalveolar LavageCellsChronicChronic BronchitisChronic Obstructive Pulmonary DiseaseCiliaClustered Regularly Interspaced Short Palindromic RepeatsCore-Binding FactorCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorDataDeacetylaseDevelopmentDiseaseEpithelial CellsEtiologyEventFeedbackFrequenciesFunctional disorderGene ExpressionGenesGoalsGoblet CellsHIVHIV ReceptorsHumanHyperplasiaImmediate-Early ProteinsImpairmentIncidenceIndividualInflammationInterventionLeadLiquid substanceLungLung diseasesLung infectionsMUC5AC geneMediatingMicroRNAsMorbidity - disease rateMucociliary ClearanceMucous body substancePathologicPathologyPathway interactionsPatientsPeptide HydrolasesPersonsPlayPublishingPulmonary InflammationQuality of lifeRecurrenceRespiratory Tract InfectionsRiskRisk FactorsRoleSIRT1 geneSeveritiesSignal TransductionSiteSmokerSmokingSmoking StatusSystemTGFB1 geneTestingThinnessUntranslated RegionsUp-RegulationViral Load resultairway epitheliumairway surface liquidantagonistantiretroviral therapybronchial epitheliumchronic respiratory diseasecigarette smokecilium biogenesiscomorbiditycytokineexposure to cigarette smokeimprovedlung microbiomemicrobial colonizationmortalitymucus clearancemucus hypersecretionnotch proteinnovelpathogenpollutantpreservationpulmonary functionpulmonary function declinerespiratory colonizationtherapeutic evaluation
项目摘要
PROJECT SUMMARY
People living with HIV demonstrate increased incidence of lung inflammation and HIV is an independent risk
factor development of COPD. HIV Tat, an immediate early protein of HIV and cigarette smoke suppress the
deacetylase SIRT1 that regulates ADAM17, a protease involved in activating Notch signaling as well as
proteolytic cleavage and activation of proinflammatory cytokines. This can lead to downstream deleterious
effects on ciliogenesis, mucociliary clearance and lung function decline. While chronic inflammation in COPD is
a multifactorial etiology, impaired mucociliary clearance leading to recurrent lung infections can play an important
role in promoting lung inflammation. Optimal mucociliary clearance requires mucus, cilia, and a thin layer of
airway surface liquid to facilitate ciliary beating. Abnormalities in any compartment of the mucociliary system can
compromise mucus clearance leading to mucus impaction entrapping bacteria and promoting chronic bacterial
infection.
HIV Tat promotes an aberrant microRNAome in the primary bronchial epithelium and upregulates miR-142-5p,
a microRNA known to suppress SIRT1. This proposal will identify mechanisms involved in HIV Tat promotes
mucociliary dysfunction and identifying individual effects on ciliogenesis, mucus hypersecretion and
inflammation. Given the causal role for SIRT1 suppression in mediating these effects, we will use a novel
CRISPR-mediated gene specific microRNA antagonism approach to disrupt the miR-142-5p target site on the
SIRT1 3’UTR. This will preserve SIRT1 expression in the context of HIV Tat and cigarette smoke without affecting
other functions of miR-142-5p. Aim 1: HIV Tat upregulates miR-142-5p and suppress SIRT1 exacerbate
upregulates ADAM17 levels by HIV and cigarette smoke exposure in NHBE ALI cultures. Given that HIV Tat and
cigarette smoke mediated miR-142-5p dysregulation leading to SIRT1 suppression and aberrant Notch signaling.
Specifically, we will analyze ADAM17 upregulation, ciliogenesis, goblet cell hyperplasia and ciliary beat
frequency in NHBE ALI cultures. Aim 2: Since HIV Tat and cigarette smoke suppresses SIRT1, and SIRT1
suppression impairs mucociliary clearance apparatus, we will determine if gene-specific microRNA antagonism
in combination with SIRT1 activator to rescue SIRT1 levels, suppression of inflammation and enhance
mucociliary clearance apparatus in primary bronchial epithelial cells treated with HIV Tat and exposed to
cigarette smoke.
项目总结
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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Srinivasan Chinnapaiyan其他文献
Srinivasan Chinnapaiyan的其他文献
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{{ truncateString('Srinivasan Chinnapaiyan', 18)}}的其他基金
Restoring mucociliary clearance apparatus to mitigate lung inflammation in the context of HIV and cigarette smoke
恢复粘膜纤毛清除装置以减轻艾滋病毒和香烟烟雾背景下的肺部炎症
- 批准号:
10664021 - 财政年份:2022
- 资助金额:
$ 14.75万 - 项目类别:
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