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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：
Celeste M Nelson
金额：
$ 55.33万
依托单位：
PRINCETON UNIVERSITY
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：
https://reporter.nih.gov/project-details/10367647
关键词：
Address Affect Air Anabolism Biochemical Biological Models Birth Breathing Cells Chest Congenital Abnormality Congenital diaphragmatic hernia Critical Care Data Defect Development Embryo Environment Epithelial Equilibrium Fetal Tissues Gene Expression Profile Genetic Transcription Growth Image Image Analysis Immunofluorescence Immunologic Immunohistochemistry In Situ Hybridization Investigation Knock-out Knockout Mice Lead Liquid substance Long-Term Survivors Lung Lung diseases Measurement Measures Mechanical Stress Mechanics Mesenchyme Mesothelium Microfluidics Molecular Morbidity - disease rate Morphogenesis Mus Neonatal Mortality Nutritional Pathogenesis Pathway interactions Pattern Phenocopy Publishing Reporter Research Design Respiratory Diaphragm Retinoids Reverse Transcriptase Polymerase Chain Reaction Rodent Model Role Secondary to Signal Pathway Signal Transduction System Testing Time Tissues Transgenic Mice Transgenic Organisms Trees Tretinoin Work airway epithelium experience fetal fluidity force sensor innovation lung development lung imaging mechanical force mechanical signal mortality mouse model neonate new therapeutic target novel pressure pulmonary hypoplasia quantitative imaging respiratory smooth muscle response sensor single-cell RNA sequencing spatiotemporal transcriptomics

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