FGF Signaling in Lung Maturation and Response to Injury

FGF 信号在肺成熟和损伤反应中的作用

基本信息

批准号：
8460835
负责人：
Xin Sun
金额：
$ 40.92万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-20 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8460835
关键词：
Adverse effects Affect Alveolar Alveolus Amphiregulin Animal Model Asthma Binding Biology Birth Weight Blood Vessels Bronchopulmonary Dysplasia Cells Child Childhood Chronic Data Defect Development Disease EGF gene Elastin Elastin Fiber Etiology Event Fibroblast Growth Factor Fibroblast Growth Factor Receptors Gases Gefitinib Gene Expression Genes Genetic Genetic Predisposition to Disease Genetic Transcription Hospitalization Human Hyperoxia Individual Infant Investigation Knowledge Laboratories Lead Link Lung Lung diseases Mechanical ventilation Modeling Molecular Mus Mutant Strains Mice Myofibroblast Neonatal Newborn Infant Nucleic Acid Regulatory Sequences Oxygen Pathogenesis Pathology Pathway interactions Patients Perinatal Pharmaceutical Preparations Phenocopy Phenotype Play Premature Infant Process Program Development Resistance Risk Role Sampling Signal Transduction Staging Structure Supplementation Testing Three-Dimensional Imaging Trauma Virus Diseases base density gain of function insight loss of function lung injury lung maturation lung repair member migration mouse model mutant novel therapeutics premature prevent progenitor research study respiratory response response to injury scaffold therapeutic target tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Bronchopulmonary dysplasia (BPD) is a prevalent pediatric respiratory lung disease, affecting ~25% of newborns with birth weight under 1500g. BPD patients suffer chronic respiratory deficiencies and are more at risk for respiratory viral infections and the development of asthma. BPD arises as a consequence of premature disruption of the normal course of development, often compounded by lung injury incurred as a side effect of oxygen supplementation and mechanical ventilation. A key feature of BPD pathology is enlargement of alveolar space. This is accompanied by an increase in myofibroblasts and disorganization of the elastin network. Whether these remodeling events are cause or consequence of alveolar enlargement is not known. To elucidate the etiology of BPD, we propose experiments in mouse models to determine the causal relationship of these defects. Existing data show fibroblast growth factor (FGF) signaling is reduced in BPD lungs, and reduction of FGF signaling in mice leads to BPD-like phenotypes. These findings suggest that FGF pathway mutant mice provide an entry point for the investigation of how BPD-like defects arise. Using these mutants, we will dissect the precise temporal and spatial requirements for FGF signaling in the perinatal period, and its precise role in lung maturation (Aim 1). We will tes the relationship between FGF and other factors implicated in lung maturation process (Aim 2). Finally, we will test whether heritable changes in FGF and FGF regulated pathways may underlie the known genetic predisposition to BPD. Our findings will not only advance basic knowledge of understudied aspects of lung biology, but will also provide insights at a molecular level of how deviation from the normal development program and external trauma may lead to the onset of BPD.

描述（由申请人提供）：支气管肺发育不良 (BPD) 是一种常见的小儿呼吸道肺部疾病，影响约 25% 的出生体重低于 1500 克的新生儿。 BPD 患者患有慢性呼吸系统缺陷，并且更容易发生呼吸道病毒感染和哮喘。 BPD 是由于正常发育过程过早中断而产生的，通常还因补充氧气和机械通气的副作用而引起的肺损伤而加剧。 BPD 病理学的一个关键特征是肺泡腔扩大。这伴随着肌成纤维细胞的增加和弹性蛋白网络的瓦解。这些重塑事件是肺泡扩大的原因还是结果尚不清楚。为了阐明 BPD 的病因，我们建议在小鼠模型中进行实验，以确定这些缺陷的因果关系。现有数据显示，BPD 肺部的成纤维细胞生长因子 (FGF) 信号传导减少，而小鼠中 FGF 信号传导的减少会导致类似 BPD 的表型。这些发现表明，FGF 通路突变小鼠为研究 BPD 样缺陷如何产生提供了一个切入点。利用这些突变体，我们将剖析围产期 FGF 信号传导的精确时间和空间需求，及其在肺成熟中的精确作用（目标 1）。我们将测试 FGF 与肺成熟过程中涉及的其他因素之间的关系（目标 2）。最后，我们将测试 FGF 和 FGF 调节途径的遗传变化是否可能是已知的 BPD 遗传易感性的基础。我们的研究结果不仅将增进肺生物学方面的基础知识，而且还将在分子水平上提供关于偏离正常发育程序和外部创伤如何导致 BPD 发作的见解。