How Dose Androgen Inhibit Fetal Maturation

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DESCRIPTION (provided by applicant): Respiratory distress syndrome of the neonate (RDS) is the leading cause of morbidity and mortality in premature infants, and remains a leading cause of infant mortality in the US, despite the advances of prenatal steroid and neonatal exogenous surfactant replacement. An improved understanding of the mechanisms controlling fetal lung maturation is needed to develop novel improved therapies to prevent and/or treat RDS. Fibroblast-type II cell communication has long been recognized as an important regulatory process in maturation of surfactant synthesis, but only in the last few years have advances been made in deciphering the mechanisms of this communication. In the previous funding period we showed that the growth factor Neuregulin (NRG), a ligand for the ErbB3 and ErbB4 receptors, is produced by fetal lung fibroblasts and stimulates type II cell surfactant synthesis. In this application we propose to further identify the molecular mechanisms controlling fibroblast-type II cell communication and learn how these mechanisms are positively and negatively regulated. We hypothesize that ErbB4, acting in heterodimers with other ErbB receptors, controls fibroblast-type II cell communication and surfactant synthesis. To test this we will focus on determining how NRG is produced in the fetal lung fibroblast, how ErbB4-containing dimers are activated and how androgen acts to interrupt this signaling process. We propose three specific aims. Specific Aim 1: Test the hypothesis that activation of TACE in fetal lung fibroblasts is a necessary step for fibroblast-type II communication. Specific Aim 2: Test the hypothesis that fibroblast-type II cell communication involves canonical type II cell ErbB4 receptor signal pathways as opposed to translocation of ErbB4 to the nucleus. Specific Aim 3: Test the hypothesis that androgen acts via transforming growth factor beta (TGF¿) to delay the induction of surfactant synthesis by increasing p66Shc protein and activation, down regulating TACE production by fibroblasts and ErbB4 signaling in type II cells. The significance of this work lies in developing a mechanistic understanding of the molecular events involved in fibroblast-type II cell differentiation controlling fetal lung maturation. Such an understanding will allow the development of novel approaches to preventing and treating RDS.