Wnt Signaling in Bronchopulmonary Dysplasia
支气管肺发育不良中的 Wnt 信号转导
基本信息
- 批准号:10226945
- 负责人:
- 金额:$ 14.84万
- 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:2019-08-15 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAGTR2 geneAXIN2 geneAffectAlveolarAlveolusAnimalsAutomobile DrivingAwardBindingBronchopulmonary DysplasiaCellsChemosensitizationCoculture TechniquesComplicationDataDevelopmentDevelopment PlansDiseaseEnvironmental Risk FactorEpithelialEpithelial CellsFamilyFibroblastsFibrosisFoundationsGenesGoalsGrowthHealth Care CostsHumanHyperoxiaImpairmentIn VitroInfantInflammationInformaticsInjuryKnowledgeLigandsLungLung diseasesMechanicsMediatingMediator of activation proteinMesenchymalModelingMolecularMusNewborn InfantNuclearPathogenesisPathway interactionsPatientsPatternPhenotypePhosphorylationPhysiciansPlayPregnancyPremature BirthPremature InfantProductivityPublicationsReporterResearchResearch PersonnelRiskRoleScientistSecond Messenger SystemsSignal PathwaySignal TransductionSpecificityStretchingStructureStructure of parenchyma of lungStudy modelsSurvivorsTerm BirthTestingTrainingTraining ProgramsTransforming Growth FactorsUp-RegulationWNT Signaling PathwayWorkalveolar epitheliumbeta catenincareer developmentcell typechemical geneticscurative treatmentsexperienceexperimental studygenetic approachhigh riskhuman modelimprovedin vitro Modelin vivointerstitiallung developmentlung injurymouse modelpreventprogramspromoterrespiratoryresponseresponse to injurysingle-cell RNA sequencingtargeted treatmenttranscription factor
项目摘要
PROJECT SUMMARY
Bronchopulmonary dysplasia (BPD) is a leading complication of preterm birth, with long term sequelae in
survivors and no curative treatment. The molecular mechanisms that promote the BPD phenotype of impaired
alveolarization and fibrosis are not known, and this knowledge gap impedes the development of new BPD
therapies. BPD primarily affects preterm infants born during the vulnerable saccular stage of lung development
(23-32 weeks gestation), with resulting injury from hyperoxia, inflammation, and mechanical stretch. Our prior
work has focused on understanding how saccular stage injury disrupts the normal patterning of developmental
pathways. One of these signaling pathways, Wnt, has peak activation in the canalicular stage and gradually
decreases during the saccular stage, with little active Wnt signaling present at term birth. We recently
demonstrated aberrant activated Wnt signaling in the lungs of infants with BPD. Moreover, exogenous
activation of Wnt signaling in our 3D human model and our hyperoxia mouse model is sufficient to reproduce
the BPD phenotype in vitro and ex vivo, suggesting that Wnt is an important driver of BPD pathogenesis.
Transforming growth factor-(TGF-) is another developmental pathway necessary for normal lung
development that in excess contributes to impaired alveolarization and fibrosis. Exposure of saccular stage
lung to hyperoxia injury results in increased activated Wnt and TGF- signaling, and we are able to
experimentally induce TGF- signaling by activation of Wnt alone. Our preliminary data show that hyperoxia
exposure of saccular stage lung results in increased mesenchymal expression of ligand Wnt5A as well as
increased epithelial expression of Wnt modulator r-spondin-3 (RSPO3), suggesting spatial specificity of Wnt
ligand expression in this model. We therefore hypothesize that that injury during the saccular stage of lung
development causes aberrant epithelial expression of RSPO3 and aberrant mesenchymal expression of
Wnt5A, and this increased Wnt signaling facilitates the activation of downstream TGF- signaling, resulting in
impaired alveolarization and fibrosis seen in BPD. Our specific aims are to: 1) determine the role of Wnt
signaling in mediating impaired alveolarization and fibrosis in BPD, and 2) to identify the mechanisms whereby
hyperoxia exposure results in Wnt pathway activation and up-regulation of TGF- signaling. Successful
completion of these specific aims will improve our understanding of the contribution of Wnt signaling to the
injury response in the developing lung and provide a foundation for targeted therapies to prevent BPD. Another
major objective of this proposal is to create a focused and structured career development plan that will provide
the necessary training for the researcher to become an independent physician-scientist with expertise in the
molecular mechanisms of BPD. The experiments and training program in this proposal create the structure for
the growth of an independent rigorous research program focused on developmental lung diseases.
项目总结
项目成果
期刊论文数量(0)
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Jennifer MalcolmSrygley Sucre其他文献
Jennifer MalcolmSrygley Sucre的其他文献
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{{ truncateString('Jennifer MalcolmSrygley Sucre', 18)}}的其他基金
Integrated Molecular and Cellular Drivers of Alveologenesis
肺泡发生的综合分子和细胞驱动因素
- 批准号:
10637764 - 财政年份:2023
- 资助金额:
$ 14.84万 - 项目类别:
Wnt Signaling in Bronchopulmonary Dysplasia
支气管肺发育不良中的 Wnt 信号转导
- 批准号:
10458630 - 财政年份:2019
- 资助金额:
$ 14.84万 - 项目类别:
Wnt Signaling in Bronchopulmonary Dysplasia
支气管肺发育不良中的 Wnt 信号转导
- 批准号:
10671760 - 财政年份:2019
- 资助金额:
$ 14.84万 - 项目类别: