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
在美国,酒精使用障碍影响超过1400万成年人,每年导致88,000人死亡。
长期饮酒会显著增加人们患肺部感染和急性呼吸道疾病的风险。
窘迫综合征(ARDS)。这种对损伤的敏感性增加被称为酒精性肺综合征,
是由肺免疫系统和肺泡上皮屏障功能障碍引起的。然而,
关于酒精如何影响传导气道中的上皮细胞,即气管和支气管,它们是
是肺部抵抗传染性病原体的第一道防线。我们用原代气道上皮细胞
从健康和酗酒患者中分离出来,并在体外对其进行区分,以检查酒精对人的影响
细胞屏障功能和形态。健康的分化的原代气道上皮细胞呈现鹅卵石状-
一旦单层细胞成熟,就变得不动--一种正常的气道细胞表型,
“干扰”。相比之下,从慢性酗酒者中分离的气道上皮细胞保持迁移性,
这意味着细胞处于“未堵塞”状态,因为拉伸细胞和细胞漩涡的区域出现在单层中。此外,大鼠
在乙醇存在下体外生长和分化的气管细胞保持不堵塞,而对照
单层变得堵塞。已知跨膜蛋白质连接粘附分子A(JAM-1)是一种重要的跨膜蛋白质。
A)调节上皮细胞迁移,并且它还通过控制上皮细胞的细胞旁流动来调节屏障功能。
小分子作为紧密连接复合物的一部分。最近,我们发现大鼠和人在体外
长期暴露于酒精的分化模型的RNA和蛋白质的JAM-A表达均降低
水平和屏障功能降低。然而,慢性酒精
暴露降低JAM-A表达并影响气道上皮屏障功能,
充分阐明。已知慢性酒精暴露会激活TGF-β1,最近的证据表明TGF-β1
抑制JAM-A的表达。因此,我们假设长期饮酒的有害影响
在传导气道上皮细胞上的暴露是由于TGF-β1活化引起JAM的衰减,
一个表达式和随后的解干扰。我的研究计划旨在确定慢性酒精
暴露(可能通过TGF-β1)影响JAM-A的表达,因此影响了原发性肝癌的屏障功能。
气道上皮细胞(目标1),并确定JAM-A如何调节集体细胞迁移/细胞堵塞(目标2)。
本项目的目标是确定慢性酒精暴露导致屏障的靶向途径
传导气道上皮细胞的功能和细胞迁移缺陷。
项目成果
期刊论文数量(0)
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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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