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

描述（由申请人提供）：目前的干预和治疗还不能显著降低支气管肺发育不良（一种囊状肺和肺泡肺发育异常的慢性疾病）的发病率。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。细菌内毒素抑制胎鼠肺囊状气道分支。内毒素暴露会降低FGF-10的表达，FGF-10是气道分支和肺发育的关键生长因子。本研究验证了内毒素释放炎症介质抑制胎儿小鼠肺中FGF-10表达的假设，导致囊状气道分支异常，并导致支气管肺发育不良。Aim 1将严格测试是否减少的FGF-10是内毒素暴露观察到的异常肺发育的原因。目的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。化学抑制NF-(B)和NF-(B)信号缺陷的基因工程小鼠品系将测试该途径是否需要抑制FGF-10。此外，使用内毒素条件介质和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发育的下游作用。然后，Aim 3将开发新的实验模型，以测试发育中的肺中特定细胞类型的NF- B激活和炎症信号是否需要FGF-10表达降低和肺形态发生异常。因此，本研究旨在测试炎症介导的FGF-10缺失是否会导致胎儿肺部发育异常，并可能导致早产儿慢性肺病。项目简介：本研究旨在研究导致支气管肺发育不良的潜在分子机制，支气管肺发育不良是困扰早产儿的一种重要疾病。在美国，每年有多达10,000例新的支气管肺发育不良病例，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.