Molecular Analysis of Airway Secretory Cells in Health and Disease
健康和疾病中气道分泌细胞的分子分析
基本信息
- 批准号:10592181
- 负责人:
- 金额:$ 10.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAlveolarAnatomyBioinformaticsBiological AssayBiologyBronchiolesBronchitisCause of DeathCellsCessation of lifeChronic BronchitisChronic Obstructive Pulmonary DiseaseClinicalDataDevelopmentDiameterDiseaseDisease ProgressionDisease modelDistalElementsEnvironmentEpithelial CellsEpitheliumEtiologyFamily suidaeFoundationsFunctional disorderGelGene Expression ProfilingGenesGeneticGoalsHealthHomeostasisHumanImpairmentIn VitroInflammationKnowledgeLabelLearningLinkLungMUC5B geneMaintenanceMentorsMolecular AnalysisMucinsMucous body substanceMusNatural regenerationObstructionOrganoidsPancreatic ElastasePathogenesisPathogenicityPathologicPathway interactionsPhasePhenotypePolymersPositioning AttributeProductionPublishingPulmonary EmphysemaRegulator GenesResearchResearch PersonnelSecretory CellSignal PathwayStructureSymptomsTamoxifenTerminal BronchioleTestingTissuesTrainingTransgenic OrganismsVeinsX-Ray Computed Tomographyairway epitheliumairway inflammationairway obstructionalveolar destructionalveolar type II cellcareercareer developmentimprovedin vivointerestlung developmentlung repairmortalitymouse modelmucus hypersecretionnovelnovel therapeuticsoverexpressionpreventprimary endpointprogenitorpulmonary functionrepairedsingle-cell RNA sequencingsmall airways diseasestem cell functionstem cellstissue repairtranslational study
项目摘要
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the US and worldwide,
and it remains
disease
incurable in part due to an incomplete understanding of its cellular mechanisms. Small airway
(SAD) and emphysema are important pathological phenotypes of COPD. SAD is characterized by
excessive mucus production and reduced alveolar attachment in the small airways (<2mm in diameter). SAD
may also worsen emphysema, the progressive destruction of alveolar tissue. However, the mechanisms
underlying the pathogenesis of small airway mucin overproduction and alveolar destruction are not well
understood. Importantly, mucin is produced by an epithelial progenitor, the club cell, which can differentiate into
alveolar type II cells for tissue repair. Here, we have discovered that overproduction of a polymeric gel-forming
mucin MUC5B may be linked to impaired alveolar regeneration by club cells in a murine COPD model. Therefore,
this proposal aims to test the central hypothesis that alveolar maintenance and repair by club cells in health
and COPD is dependent on MUC5B expression. Specific Aim 1 will test the hypothesis that MUC5B
expression inhibits differentiation of club cells into ATII cells during homeostasis. I will employ organoid assays
to test steady state progenitor functions of MUC5B-expressing and non-expressing club cells from healthy mice
with tamoxifen-induced lineage tracing of club cells and fluorescent labeling of endogenous MUC5B. Further
studies will employ mice with genetic deficiency or transgenic overexpression of Muc5b. Specific Aim 2 will test
the hypothesis that overproduction of MUC5B inhibits alveolar repair in a mouse model of COPD. Mice from Aim
1 will be treated with porcine pancreatic elastase (PPE) to test whether excessive MUC5B in club cells impairs
alveolar differentiation in vitro and in vivo, and whether conditional depletion of Muc5b ameliorates SAD and
emphysema. Finally, Specific Aim 3 will test the hypothesis that disrupting stimulated mucin overproduction
prevents SAD and emphysema by restoring progenitor function of club cells. I will investigate the mechanism of
how extra- versus intra-cellular excessive MUC5B impairs progenitor functions of club cells, and I will identify
novel genes that regulate club cell mucous and progenitor functions and expand on translational studies in
human COPD. These studies will fill gaps in our knowledge of heterogeneous functions of club cells in small
airways in homeostasis and disease. Aim 1, 2 and part of Aim 3 will be completed during the K99 training phase.
Key elements of my training will be learning new fields of mucin biology and bioinformatics that will help me
develop my career as a translational COPD researcher. Results of my studies will supply a foundation for strong
lines of independent research on pathways regulating epithelial phenotypes in COPD and development of novel
therapeutics for SAD and emphysema in the R00 phase. With my outstanding mentoring team and an
exceptional training environment, I am ideally positioned to achieve the proposed scientific training and career
development goals and mature into an independent investigator.
慢性阻塞性肺疾病(COPD)是美国乃至全世界第三大死因,
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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Yan Hu其他文献
Yan Hu的其他文献
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{{ truncateString('Yan Hu', 18)}}的其他基金
Identification of a Wnt/ Beta-catenin responsive adult lung epithelial progenitor cell for tissue repair in chronic lung disease
鉴定用于慢性肺病组织修复的 Wnt/β-连环蛋白反应性成人肺上皮祖细胞
- 批准号:
10001340 - 财政年份:2019
- 资助金额:
$ 10.85万 - 项目类别:
Identification of a Wnt/ Beta-catenin responsive adult lung epithelial progenitor cell for tissue repair in chronic lung disease
鉴定用于慢性肺病组织修复的 Wnt/β-连环蛋白反应性成人肺上皮祖细胞
- 批准号:
10231191 - 财政年份:2019
- 资助金额:
$ 10.85万 - 项目类别:
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