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FGF18 regulation of postnatal lung development

FGF18 调节产后肺部发育

基本信息

批准号：
10444913
负责人：
David M Ornitz
金额：
$ 62.51万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10444913
关键词：
Adult Air Alveolar Alveolar wall Alveolus Apoptotic Area Atlases Blood Vessels Blood capillaries Blood gas Bronchopulmonary Dysplasia Cell Differentiation process Cell Maturation Cell Nucleus Cell Separation Cells Communities Complication Coupled Defect Development Disease Elastin Embryo Ensure Epithelial Epithelial Cells Extracellular Matrix FGFR3 gene FGFR4 gene Fibroblast Growth Factor Fibroblasts Gases Gene Expression Gene Silencing Genetic Health Human Impairment Knowledge Ligands Lung Mesenchymal Mesenchymal Stem Cells Mesenchyme Molecular Mus Myofibroblast Neonatal Organ Pharmacological Treatment Phase Population Premature Birth Premature Infant Process Production Proliferating RNA Regulation Research Resources Rodent Saccule structure Signal Transduction Signaling Molecule Source Structure Supportive care Surface Thinness Vitamin A base cell type chronic respiratory disease deep sequencing experimental study fibroblast growth factor 18 improved outcome infant outcome lung development lung regeneration novel postnatal progenitor programs response therapy development tool transcriptome sequencing

项目摘要

Title: FGF18 regulation of postnatal lung development Summary: Alveologenesis is the final stage of lung development where the surface area of the lung is increased by subdividing alveolar saccules through the formation of secondary septae (septal ridges), followed by thinning of the septal walls to generate an efficient air/blood gas exchange organ. Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth in which alveologenesis is impaired. BPD often results in chronic respiratory disease. However, besides Vitamin A and supportive care, no therapies exist to promote lung alveolar and vascular development to improve the outcomes of infants with BPD. Alveologenesis can be divided into two phases in humans and rodents. During the first phase, alveolar myofibroblasts (AMFs) and other mesenchymal and epithelial cells regulate the formation of secondary septae. During the second phase, the septal walls undergo a maturation process that involves thinning, through loss of mesenchymal cells and remodeling of the microvasculature, to a single layer capillary network juxtaposed with alveolar type 1 (AT1) cells. The mature alveolar wall ensures efficient air/blood gas exchange in the adult lung. An in-depth understanding the mechanisms that regulate alveolar septation and septal wall maturation will be required to develop therapies for premature infants with BPD and for developing potential therapies for adult lung regeneration. However, there are specific knowledge gaps about the identity of mesenchymal progenitors that give rise to AMFs, the functions of AMFs and other mesenchymal cell types, and the mechanisms that terminate and clear AMFs from the lung at the completion of secondary septation. Fibroblast Growth Factor 18 (Fgf18) is expressed at high levels in AMFs and AT1 cells during alveologenesis. We show that conditional inactivation of Fgf18 in the neonatal lung results in impaired alveologenesis. Through lineage tracing of Fgf18-expressing cells, we find that the AMFs are cleared from the lung after the first phase of alveologenesis, coinciding with alveolar wall thinning, but that AT1 cells are retained. In this proposal, we use a combination of unique genetic tools for lineage tracing and gene inactivation, cell sorting coupled with RNA deep sequencing, and single cell and single nuclei RNA sequencing, to identify the relative contribution of mesenchymal and epithelial FGF18 to the first and second phases of alveologenesis, the cellular response(s) to FGF18 during alveologenesis, the progenitors that give rise to fibroblasts sub-types in alveolar septae, and the mechanisms that specifically clear AMFs from the lung. The proposed experiments will also generate an atlas of gene expression for septal mesenchymal cell types present during alveologenesis that will serve as a resource for the research community.

标题：FGF18对出生后肺发育的调节