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.
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