Interplay between mechanical forces and retinoic acid in lung development
肺发育中机械力和视黄酸之间的相互作用
基本信息
- 批准号:10367647
- 负责人:
- 金额:$ 55.33万
- 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:2022-01-01 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAirAnabolismBiochemicalBiological ModelsBirthBreathingCellsChestCongenital AbnormalityCongenital diaphragmatic herniaCritical CareDataDefectDevelopmentEmbryoEnvironmentEpithelialEquilibriumFetal TissuesGene Expression ProfileGenetic TranscriptionGrowthImageImage AnalysisImmunofluorescence ImmunologicImmunohistochemistryIn Situ HybridizationInvestigationKnock-outKnockout MiceLeadLiquid substanceLong-Term SurvivorsLungLung diseasesMeasurementMeasuresMechanical StressMechanicsMesenchymeMesotheliumMicrofluidicsMolecularMorbidity - disease rateMorphogenesisMusNeonatal MortalityNutritionalPathogenesisPathway interactionsPatternPhenocopyPublishingReporterResearch DesignRespiratory DiaphragmRetinoidsReverse Transcriptase Polymerase Chain ReactionRodent ModelRoleSecondary toSignal PathwaySignal TransductionSystemTestingTimeTissuesTransgenic MiceTransgenic OrganismsTreesTretinoinWorkairway epitheliumexperiencefetalfluidityforce sensorinnovationlung developmentlung imagingmechanical forcemechanical signalmortalitymouse modelneonatenew therapeutic targetnovelpressurepulmonary hypoplasiaquantitative imagingrespiratory smooth muscleresponsesensorsingle-cell RNA sequencingspatiotemporaltranscriptomics
项目摘要
PROJECT SUMMARY
Breathing after birth requires coordinated development of the airway epithelium and its surrounding
mesenchyme and mesothelium. In the fetus, these tissues form in response to exogenous forces from fluid
pressure within and around the developing lungs that is normally high in the lumen of the airways, thus
generating a positive transpulmonary pressure. The mechanical environment of the fetal chest cavity is
disrupted by conditions such as congenital diaphragmatic hernia (CDH), which reduces or reverses the
pressure across the developing lungs and leads to pulmonary hypoplasia, a major cause of neonatal mortality.
Although several biochemical signals, including retinoic acid (RA), have been implicated in the pathogenesis of
CDH, the mechanical forces and signaling downstream of transpulmonary pressure that regulate lung
development are unknown. Our preliminary and published data suggest that transpulmonary pressure itself
regulates the RA-biosynthesis pathway, airway epithelial branching morphogenesis, and airway smooth
muscle differentiation. Here, we propose to take advantage of our innovative microfluidic platforms, tissue-
specific knockout mice, fluorescent reporter mice, and mouse models of CDH to uncover the molecular
mechanisms that connect pressure, RA signaling, and morphogenesis and differentiation within the embryonic
lung. We will combine these approaches with time-lapse imaging of lung explants, single-cell transcriptomic
analysis, and real-time fluorescent force sensors. In Specific Aim 1, we will test the hypothesis that pressure
activates the mechanosensor Yap in a tissue-specific manner to regulate the spatiotemporal pattern of
expression of genes involved in the RA-biosynthesis pathway. In Specific Aim 2, we will uncover the effects of
pressure and tissue-specific synthesis of RA on airway epithelial growth and morphogenesis and airway
smooth muscle differentiation. In Specific Aim 3, we will measure the relative effects of pressure and RA
signaling on tension, strain, and fluidity within the epithelium, mesenchyme, and mesothelium. This work will,
for the first time, identify the tissue-specific mechanical forces and molecular signaling downstream of
transpulmonary pressure that regulate early morphogenesis of the lung. We expect that our findings will
suggest novel therapeutic targets for the treatment of defects in lung development.
项目总结
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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Celeste M Nelson其他文献
Microstructured Extracellular Matrices in Tissue Engineering and Development This Review Comes from a Themed Issue on Tissue and Cell Engineering Edited Why Introduce Structure into Ecms? Methods for Patterning Ecms Ecms for Tissue Engineering Ecms for the Study of Development
组织工程和发育中的微结构细胞外基质这篇综述来自组织和细胞工程的主题问题编辑为什么将结构引入 Ecms?
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
Celeste M Nelson;Joe Tien;J L Sherley - 通讯作者:
J L Sherley
Dynamics of branched tissue assembly
- DOI:
10.1186/scrt133 - 发表时间:
2012-10-31 - 期刊:
- 影响因子:7.300
- 作者:
Sriram Manivannan;Celeste M Nelson - 通讯作者:
Celeste M Nelson
Celeste M Nelson的其他文献
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{{ truncateString('Celeste M Nelson', 18)}}的其他基金
Interplay between mechanical forces and retinoic acid in lung development
肺发育中机械力和视黄酸之间的相互作用
- 批准号:
10545087 - 财政年份:2022
- 资助金额:
$ 55.33万 - 项目类别:
Mechanical Forces and the Regulation of Airway Progenitor Cells
机械力和气道祖细胞的调节
- 批准号:
9788586 - 财政年份:2019
- 资助金额:
$ 55.33万 - 项目类别:
Mechanical Forces and the Regulation of Airway Progenitor Cells
机械力和气道祖细胞的调节
- 批准号:
10665548 - 财政年份:2019
- 资助金额:
$ 55.33万 - 项目类别:
Mechanical Forces and the Regulation of Airway Progenitor Cells
机械力和气道祖细胞的调节
- 批准号:
10429986 - 财政年份:2019
- 资助金额:
$ 55.33万 - 项目类别:
Mechanical Forces and the Regulation of Airway Progenitor Cells
机械力和气道祖细胞的调节
- 批准号:
10198967 - 财政年份:2019
- 资助金额:
$ 55.33万 - 项目类别:
Engineered invasive human breast tumors with integrated capillaries and lymphatics
具有集成毛细血管和淋巴管的工程侵袭性人类乳腺肿瘤
- 批准号:
9912555 - 财政年份:2017
- 资助金额:
$ 55.33万 - 项目类别:
Engineered Invasive Human Breast Tumors with Integrated Capillaries and Lymphatics
具有集成毛细血管和淋巴管的工程侵袭性人类乳腺肿瘤
- 批准号:
9888360 - 财政年份:2017
- 资助金额:
$ 55.33万 - 项目类别:
Mechanical Regulation of Mesenchyme and Mammalian Lung Development
间充质和哺乳动物肺发育的机械调节
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9307949 - 财政年份:2014
- 资助金额:
$ 55.33万 - 项目类别:
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