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: 7466696
• 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/7466696
• 关键词: Alveolar; Amniotic Fluid; Antibodies; Area; Bronchopulmonary Dysplasia; Cells; Chemicals; Childhood; Chronic Disease; Chronic lung disease; Communication; Condition; 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; Inflammatory; Intervention; Investigation; Lead; Lipopolysaccharides; Lung; Measures; Mediating; Mediator of activation protein; Membrane; Mesenchymal; Mesenchyme; Modeling; Molecular; Morbidity - disease rate; Morphogenesis; Mouse Strains; Mus; 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）：目前的干预措施和治疗方法无法显着降低支气管肺发育不良的发生率，这是一种异常的糖尿病和肺泡肺发育的慢性疾病。因此，研究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。产前暴露于绒毛膜膜炎（孕产妇膜，胎盘和子宫的炎症）增加了早产儿的支气管肺发育异常的风险。绒毛膜膜炎的实验小鼠模型将允许研究炎症信号如何改变胎儿肺发育。细菌内毒素抑制胎儿小鼠肺中的Saccular气道分支。内毒素暴露降低了FGF-10的表达，FGF-10是气道分支和肺发育的关键生长因子。该提案检验了以下假设：内毒素释放炎症介质抑制胎儿肺中FGF-10表达的炎症介质，导致sAccular Airway Airway分支异常，并导致支气管肺发育异常。 AIM 1如果减少FGF-10是导致内毒素暴露观察到的异常肺发育，将严格测试。 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然后，内毒素对肺发育的下游影响。婴儿叙事：该提案研究了导致支气管肺发育不良的潜在分子机制，这是一种重要的疾病。在美国，每年多达10,000例新的支气管肺发育不良病例，使其成为童年最常见和最昂贵的疾病之一。