How Does Androgen Inhibit Fetal Maturation

描述(由申请人提供)：新生儿呼吸窘迫综合征(RDS)是早产儿发病率和死亡率的主要原因，尽管产前类固醇和新生儿外源性表面活性物质替代技术取得了进展，但在美国，RDS仍然是导致婴儿死亡的主要原因。需要更好地了解控制胎儿肺成熟的机制，以开发新的改进疗法来预防和/或治疗RDS。成纤维细胞-II型细胞通讯一直被认为是表面活性物质合成成熟的重要调节过程，但直到最近几年才在破译这种通讯机制方面取得了进展。在之前的资助期间，我们已经证明了生长因子神经调节蛋白(NRG)是ErbB3和ErbB4受体的配体，由胎肺成纤维细胞产生，刺激II型细胞表面活性物质的合成。在这一应用中，我们建议进一步确定控制成纤维细胞II型细胞通讯的分子机制，并了解这些机制是如何正向和负向调节的。我们推测，ErbB4与其他ErbB受体以异二聚体的形式作用，控制成纤维细胞与II型细胞的通讯和表面活性物质的合成。为了测试这一点，我们将重点确定NRG是如何在胎肺成纤维细胞中产生的，含有ErbB4的二聚体是如何被激活的，以及雄激素是如何作用于中断这一信号过程的。我们提出了三个具体目标。具体目的1：验证TACE在胎肺成纤维细胞中的激活是成纤维细胞-II型通讯的必要步骤的假说。具体目标2：验证成纤维细胞与II型细胞的通讯涉及典型的II型细胞ErbB4受体信号通路的假设，而不是ErbB4转位到细胞核的假设。具体目标3：验证雄激素通过转化生长因子β(TGFβ)通过增加p66Shc蛋白和活化、下调成纤维细胞产生TACE和下调II型细胞中ErbB4信号而延缓表面活性物质合成的假说。这项工作的意义在于从机制上理解控制胎肺成熟的成纤维细胞II型细胞分化所涉及的分子事件。这样的理解将有助于开发预防和治疗RDS的新方法。

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.