Impact of alcohol exposure on unjamming the airway epithelium
酒精暴露对疏通气道上皮的影响
基本信息
- 批准号:10447296
- 负责人:
- 金额:$ 0.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-08 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAdult Respiratory Distress SyndromeAffectAirAlcoholsAreaAttenuatedBiological AssayBreast Cancer cell lineBronchiCell NucleusCell ShapeCell modelCell physiologyCellsCessation of lifeChronicComplementary DNAComplexDefectDimerizationDiseaseDisease modelDyesElectrical ResistanceEpithelialEpithelial CellsEthanolExhibitsFocal Adhesion Kinase 1Functional disorderGene ExpressionGoalsHealthHumanImmune systemIn VitroInfectionInjuryIntegral Membrane ProteinIntercellular JunctionsLentivirusLinkLiquid substanceLungLung infectionsMAPK3 geneMeasuresMicroscopyModelingMolecularMorphologyPathway interactionsPatientsPatternPhenotypePhospho-Specific AntibodiesPhosphorylationPhysical shapePredispositionProteinsQuantitative Reverse Transcriptase PCRRNARattusRepressionResearchRiskRoleStretchingSyndromeTestingTight JunctionsTimeTracheaTransforming Growth Factor alphaUnited Statesairway epitheliumalcohol exposurealcohol responsealcohol use disorderalveolar epitheliumasthmatic patientattenuationcell motilitychronic alcohol ingestiondesignexperimental studyimprovedin vitro Modelinhibitor/antagonistjunctional adhesion moleculekeratinocytekinase inhibitorknock-downmigrationmolecular imagingmonolayernon-alcoholicpathogenproblem drinkerreceptorsmall hairpin RNAsmall moleculewound healing
项目摘要
PROJECT ABSTRACT
Alcohol use disorder affects over 14 million adults and causes 88,000 deaths each year in the United States.
Chronic alcohol use significantly increases people’s risk of developing lung infections and acute respiratory
distress syndrome (ARDS). This increased sensitivity to injury is a condition known as alcoholic lung syndrome,
and it is caused by dysfunction of the lung immune system and alveolar epithelial barrier. However, little is known
about how alcohol impacts epithelial cells in the conducting airway, i.e. the trachea and bronchi, which are the
first line of defense against infectious pathogens in the lungs. We have used primary airway epithelial cells
isolated from healthy and alcoholic patients and differentiated them in vitro to examine the impact of alcohol on
cell barrier function and morphology. Healthy differentiated primary airway epithelial cells exhibit a cobblestone-
like pattern and become immobile once the monolayer has matured— a normal airway cell phenotype known as
“jamming”. By contrast, airway epithelial cells isolated from chronic alcoholics remained migratory and in an
“unjammed” state, since areas of stretched cells and swirls of cells appear in the monolayer. Additionally, rat
tracheal cells grown and differentiated in vitro in the presence of ethanol remain unjammed while control
monolayers become jammed. It is known that the transmembrane protein junctional adhesion molecule A (JAM-
A) regulates epithelial cell migration, and it also regulates barrier function by controlling the paracellular flow of
small molecules as part of tight junction complexes. Recently, we found that both rat and human in vitro
differentiation models chronically exposed to alcohol have decreased JAM-A expression at both RNA and protein
levels and decreased barrier function compared to their control counterparts. Nevertheless, how chronic alcohol
exposure decreases JAM-A expression and impacts airway epithelial barrier function and migration has not been
fully elucidated. Chronic alcohol exposure is known to activate TGF-β1 and recent evidence has linked TGF-β1
to repression of JAM-A expression. Thus, we hypothesize that the deleterious effects of chronic alcohol
exposure on conducting airway epithelial cells are due to TGF-β1 activation causing attenuation of JAM-
A expression and subsequent unjamming. My research plan is designed to determine how chronic alcohol
exposure (potentially through TGF-β1) impacts JAM-A expression and, therefore, barrier function in primary
airway epithelial cells (Aim 1), and to define how JAM-A regulates collective cell migration/cell jamming (Aim 2).
The goal of this project is to identify targetable pathways by which chronic alcohol exposure causes barrier
function and cell migration defects in conducting airway epithelial cells.
项目摘要
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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Kristen Leigh Fowler其他文献
Kristen Leigh Fowler的其他文献
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{{ truncateString('Kristen Leigh Fowler', 18)}}的其他基金
Impact of alcohol exposure on unjamming the airway epithelium
酒精暴露对疏通气道上皮的影响
- 批准号:
10547794 - 财政年份:2021
- 资助金额:
$ 0.25万 - 项目类别:
Impact of alcohol exposure on unjamming the airway epithelium
酒精暴露对疏通气道上皮的影响
- 批准号:
10312710 - 财政年份:2021
- 资助金额:
$ 0.25万 - 项目类别:
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