FGF-10 Expression in a Fetal Mouse Lung Model of Bronchopulmonary Dysplasia

FGF-10 在支气管肺发育不良胎鼠肺模型中的表达

• 批准号: 7614450
• 负责人: Lawrence S Prince
• 金额: $ 34.54万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7614450
• 关键词: Alveolar; Amniotic Fluid; Antibodies; Area; Bronchopulmonary Dysplasia; Cells; Chemicals; Childhood; Chronic Disease; Chronic lung disease; Communication; Conditioned Culture Media; Cultured Cells; Cycloheximide; Data; Development; Disease; Endotoxins; Epithelial; Epithelium; Escherichia coli; Excision; Experimental Models; Exposure to; Fetal Lung; Fibroblast Growth Factor; Gases; Gene Expression; Genes; Genetically Engineered Mouse; Goals; Growth Factor; In Vitro; Incidence; Infant; Infection of amniotic sac and membranes; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Investigation; Lead; Lipopolysaccharides; Lung; Measures; Mediating; Membrane; Mesenchymal; Mesenchyme; Modeling; Molecular; Morbidity - disease rate; Morphogenesis; Mouse Strains; Mus; National Heart, Lung, and Blood Institute; Pathway interactions; Patients; Placenta; Premature Infant; Production; Protein Biosynthesis; Proteins; Reporter; Risk; Signal Transduction; Small Interfering RNA; Staging; Surface; TLR2 gene; Testing; Time; Transgenic Mice; United States; Uterus; airway epithelium; alveolar epithelium; cell type; cytokine; fetal; fibroblast growth factor 10; in vivo; in vivo Model; indexing; innovation; lung development; microbial; mouse model; mutant; novel; novel therapeutics; prenatal exposure; prevent; promoter; toll-like receptor 4; transcription factor

DESCRIPTION (provided by applicant): Current interventions and treatments have not been able to significantly reduce the incidence of bronchopulmonary dysplasia, a chronic disease of abnormal saccular and alveolar lung development. Novel and innovative studies investigating the causes and molecular mechanisms leading to bronchopulmonary dysplasia are therefore critical. Prenatal exposure to chorioamnionitis (inflammation of the maternal membranes, placenta, and uterus) increases the risk of bronchopulmonary dysplasia in preterm infants. Experimental mouse models of chorioamnionitis will allow investigation of how inflammatory signals might alter fetal lung development. Bacterial endotoxin inhibits saccular airway branching in fetal mouse lungs. Endotoxin exposure decreases the expression of FGF-10, a critical growth factor for airway branching and lung development. This proposal tests the hypothesis that endotoxins release inflammatory mediators that inhibit FGF-10 expression in the fetal mouse lung, leading to abnormal saccular airway branching and contributing to bronchopulmonary dysplasia. Aim 1 will rigorously test if decreased FGF-10 is responsible for the abnormal lung development observed with endotoxin exposure. Aim 2 will test if activation of the transcription factor NF-(B leads to inflammatory signals that inhibit FGF-10 expression. Chemical NF-(B inhibition and genetically engineered mouse strains with defective NF-(B signaling will test if this pathway is required for inhibiting FGF-10. Also, using endotoxin-conditioned media and preventing the release of intermediate factors will test if secondary inflammatory mediators can mediate the downstream effects of endotoxin on lung development. Aim 3 will then develop novel experimental models to test if NF-(B activation and inflammatory signaling in specific cell types in the developing lung are required for decreased FGF-10 expression and abnormal lung morphogenesis. This proposal therefore tests if inflammation-mediated loss of FGF-10 leads to abormal fetal lung development and potentially contributes to chronic lung disease in preterm infants. PROJECT NARRATIVE: This proposal investigates potential molecular mechanisms leading to bronchopulmonary dysplasia, an important disease aflicting preterm infants. Up to 10,000 new cases of bronchopulmonary dysplasia occur each year in the United States, making it one of the most common and costly diseases of childhood.

描述（由申请人提供）：目前的干预和治疗未能显着降低支气管肺发育不良的发病率，支气管肺发育不良是一种肺囊和肺泡发育异常的慢性疾病。因此，调查导致支气管肺发育不良的原因和分子机制的新颖和创新研究至关重要。产前接触绒毛膜羊膜炎（母体膜、胎盘和子宫的炎症）会增加早产儿支气管肺发育不良的风险。绒毛膜羊膜炎的实验小鼠模型将有助于研究炎症信号如何改变胎儿肺部发育。细菌内毒素抑制胎鼠肺中的囊状气道分支。内毒素暴露会降低 FGF-10 的表达，FGF-10 是气道分支和肺部发育的关键生长因子。该提案检验了这样的假设：内毒素释放炎症介质，抑制胎儿小鼠肺部的 FGF-10 表达，导致异常的囊状气道分支并导致支气管肺发育不良。目标 1 将严格测试 FGF-10 减少是否导致内毒素暴露引起的肺部发育异常。目标 2 将测试转录因子 NF-(B 的激活是否会导致抑制 FGF-10 表达的炎症信号。化学 NF-(B 抑制和具有缺陷 NF-(B 信号传导的基因工程小鼠品系) 将测试是否需要该途径此外，使用内毒素条件培养基并阻止中间因子的释放将测试继发性炎症介质是否可以介导内毒素对肺部发育的下游影响，然后将开发新的实验。模型来测试发育中肺部特定细胞类型中的 NF-(B 激活和炎症信号传导是否是 FGF-10 表达减少和肺形态发生异常所必需的。因此，该提案测试炎症介导的 FGF-10 缺失是否会导致胎儿畸形肺部发育并可能导致早产儿慢性肺部疾病。 项目叙述：该提案研究了导致支气管肺发育不良（一种困扰早产儿的重要疾病）的潜在分子机制。美国每年出现多达 10,000 例支气管肺发育不良新病例，使其成为儿童期最常见且代价最高的疾病之一。