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

描述（由申请方提供）：目前的干预和治疗尚不能显著降低支气管肺发育不良的发生率，支气管肺发育不良是一种囊状肺和肺泡肺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的研究至关重要。产前暴露于绒毛膜炎（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。绒毛膜炎的实验小鼠模型将允许研究炎症信号如何改变胎肺发育。细菌内毒素抑制胎鼠肺囊状气道分支。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。该提案测试了这样的假设：内毒素释放炎症介质，抑制胎鼠肺中的FGF-10表达，导致异常囊状气道分支并导致支气管肺发育不良。目的1将严格测试FGF-10的减少是否是内毒素暴露下观察到的异常肺发育的原因。目的2将测试转录因子NF-β B的激活是否导致抑制FGF-10表达的炎症信号。化学NF-β B抑制和具有缺陷型NF-β B信号传导的基因工程小鼠品系将测试该途径是否是抑制FGF-10所必需的。此外，使用内毒素条件培养基和阻止中间因子的释放将测试次级炎症介质是否可以介导内毒素对肺发育的下游作用。目的3将开发新的实验模型，以测试是否NF-β B激活和炎症信号在特定类型的细胞在发展中的肺所需的FGF-10表达减少和异常肺形态发生。因此，该建议测试炎症介导的FGF-10损失是否导致胎肺发育异常并可能导致早产儿的慢性肺病。项目叙述：本研究旨在探讨导致早产儿支气管肺发育不良的潜在分子机制。在美国，每年发生多达10，000例支气管肺发育不良的新发病例，使其成为儿童最常见和最昂贵的疾病之一。

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.