FGF18 regulation of postnatal lung development

FGF18 调节产后肺部发育

基本信息

批准号：
10703208
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/10703208
关键词：
Adult Air Alveolar Alveolar wall Alveolus Apoptotic Area Atlases Blood Vessels Blood capillaries Blood gas Bronchopulmonary Dysplasia Cell Differentiation process Cell Proliferation Cell Separation Cells Communities Complication Coupled Defect Development Disease Elastin Embryo Ensure Epithelial Cells Epithelium 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 RNA Regulation Research Resources Rodent Saccule structure Signal Transduction Signaling Molecule Source Structure Supportive care Surface Thinness Vitamin A 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 single nucleus RNA-sequencing therapy development tool

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产后肺发育的调节概括：肺单术是肺发育的最后阶段，肺的表面积通过通过次级隔膜的形成（间隔山脊）的细分牙槽囊，然后变薄中间壁产生有效的空气/血液交换器官。支气管肺发育不良（BPD）是早产的常见并发症，其中肺单术受到了损害。 BPD通常导致慢性呼吸道疾病。但是，除了维生素A和支持性护理外，没有疗法可促进肺肺泡和血管发育以改善BPD婴儿的结局。肺单术可以在人类和啮齿动物中分为两个阶段。在第一阶段，肺泡肌纤维细胞（AMF）和其他间质细胞和上皮细胞调节继发隔膜的形成。在第二阶段，间隔壁经历了一个成熟过程，该过程涉及通过损失而变薄间充质细胞和微脉管系统的重塑，与单层毛细管网络并列牙槽1（AT1）细胞。成熟的肺泡壁可确保成年肺中有效的空气/血气交换。深入了解调节肺泡分离和间隔壁成熟的机制将是需要开发BPD过早婴儿的疗法并为成人开发潜在疗法肺部再生。但是，关于间充质祖细胞的身份存在特定的知识差距引起AMF，AMF和其他间充质细胞类型的功能以及次级分隔完成时，肺中终止并清除AMF。成纤维细胞生长因子18（FGF18）在肺泡术期间在AMF和AT1细胞中以高水平表达。我们显示，新生儿肺中FGF18的条件失活导致肺泡术受损。通过 FGF18表达细胞的谱系追踪，我们发现AMF在第一阶段之后从肺中清除肺泡术，与肺泡壁变薄相吻合，但该AT1细胞被保留。在此提案中，我们将独特的遗传工具组合用于谱系追踪和基因失活，细胞与RNA深测序以及单细胞和单核RNA测序进行分类，以鉴定间质和上皮FGF18对肺单术的第一和第二阶段的相对贡献，肺单术期间对FGF18的细胞反应，祖细胞产生成纤维细胞亚型的祖细胞肺泡隔膜以及明确清除肺AMF的机制。提出的实验将还产生一个基因表达的地图集的基因表达，用于肺单齿中存在的间隔间充质细胞类型，将作为研究界的资源。