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

描述(申请人提供)：目前的干预和治疗未能显著降低支气管肺发育不良的发生率，这是一种囊状和肺泡发育异常的慢性疾病。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的研究是至关重要的。产前暴露于绒毛膜羊膜炎(母体胎膜、胎盘和子宫的炎症)会增加早产儿发生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可以研究炎症信号如何改变胎儿肺发育。细菌内毒素抑制胎鼠肺内囊状气道分支。暴露于内毒素可降低成纤维细胞生长因子-10的表达，成纤维细胞生长因子是呼吸道分支和肺发育的关键生长因子。这一建议验证了内毒素释放炎症介质抑制胎鼠肺中成纤维细胞生长因子-10表达的假说，导致球囊状气道分支异常，并导致支气管肺发育不良。目的1将严格检验在内毒素暴露下观察到的肺发育异常是否与成纤维细胞生长因子-10降低有关。Aim 2将测试转录因子NF-(B)的激活是否会导致炎症信号抑制成纤维细胞生长因子-10的表达。化学的核因子-B抑制和具有缺陷的核因子-(B)信号的转基因小鼠品系将测试这一途径是否是抑制成纤维细胞生长因子-10所必需的。此外，使用内毒素条件培养液和防止中间因子的释放将测试次级炎症介质是否能够中介内毒素对肺发育的下游影响。然后，Aim 3将开发新的实验模型，以测试发育中的肺组织中特定细胞类型的NF-B激活和炎症信号是否需要减少成纤维细胞生长因子-10的表达和异常的肺形态发生。因此，这项建议测试了炎症介导的成纤维细胞生长因子-10的缺失是否会导致胎儿肺发育异常，并可能导致早产儿的慢性肺部疾病。项目简介：这项提案调查了导致支气管肺发育不良的潜在分子机制，这是困扰早产儿的一种重要疾病。美国每年发生多达1万例新的支气管肺发育不良病例，使其成为最常见和最昂贵的儿童疾病之一。

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.