Molecular mechanisms of lung branching morphogenesis

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Project Summary/Abstract Neonatal respiratory distress remains an important cause of neonatal mortality and morbidity. The majority of cases are caused by surfactant deficiency and subsequent abnormality in neonatal respiratory adaptation. However, the causative mechanisms leading to impaired perinatal lung maturation and surfactant deficiency are not fully understood. Our preliminary studies suggest that BMP signaling is critical to neonatal respiration, and may also contribute to glucocorticoid-augmented surfactant protein expression. Determination of the related mechanisms of BMP signaling in enhancing perinatal lung maturation and adaptation, as well as in mediating antenatal glucocorticoid's stimulatory effects on lung growth will help to break through the critical barrier for prevention and treatment of neonatal respiratory distress. Thus, we propose three specific aims to test the Hypothesis: BMP signaling in peripheral lung epithelial cells is essential for perinatal lung maturation and neonatal respiratory adaptation by promoting endogenous surfactant production through upregulating Nfatc3 and Lpcat1 expression, which in turn contributes to glucocorticoid-enhanced lung maturation. Thus, deficient BMP signaling may result in neonatal respiratory failure. Aim 1. To determine whether BMP signaling in peripheral lung epithelial cells is essential for perinatal lung maturation and neonatal respiratory adaptation. Dynamic changes in BMP signaling activity will be determined in association with surfactant production and function during perinatal mouse lung growth and adaptation. The role of BMP signaling in neonatal respiration will be defined in vivo by genetically deleting BMP receptor (Alk3) or downstream Smad1, or by administering a small molecule inhibitor specifically against BMP receptor Alk3 in mice. In addition, the efficacy of therapeutic application of BMP signal activation to increase surfactant production in perinatal mouse lung tissue will also be determined by exogenous BMP4 administration or by induction of constitutively active Alk3 transgenic overexpression. Aim 2. To determine the transcriptional regulatory mechanisms by which BMP signaling positively regulates Nfatc3 and Lpcat1 expression. Our preliminary data suggest that BMP-Smad1 may directly regulate gene expression of Nfatc3 and Lpcat1, which are important in promoting surfactant protein expression and phosphatidylcholine synthesis. Therefore, the transcriptional regulatory mechanisms of these genes by Smad1, including Smad1-promoter DNA interaction, will be determined in perinatal lung epithelial cells. Aim 3. To determine the role of BMP signaling in mediating glucocorticoid effects on promoting perinatal lung maturation. Whether glucocorticoid treatment enhances the pulmonary BMP signaling pathway will be determined in vivo. The role of BMP pathway activation in mediating glucocorticoid stimulatory effects on surfactant production will then be determined in perinatal mice with Alk3 or Smad1 gene knockout. Related molecular mechanisms will be dissected in alveolar epithelial cells.