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，并且在美国仍然是婴儿死亡的主要原因，尽管产前类固醇和新生儿外源性表面活性剂替代取得了进展。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剂合成成熟的重要调控过程，但直到最近几年，在解读这种通讯机制方面才取得进展。在之前的资助期内，我们发现生长因子神经调节蛋白（NRG）是ErbB3和ErbB4受体的配体，由胎儿肺成纤维细胞产生并刺激II型细胞表面活性物质的合成。在这项应用中，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被积极和消极调节的。我们假设ErbB4与其他ErbB受体以异源二聚体的形式作用，控制成纤维细胞II型细胞的通讯和表面活性剂的合成。为了验证这一点，我们将重点确定NRG是如何在胎儿肺成纤维细胞中产生的，含erbb4的二聚体是如何被激活的，以及雄激素是如何阻断这一信号传导过程的。我们提出三个具体目标。具体目的1：验证胎儿肺成纤维细胞中TACE的激活是成纤维细胞II型通讯的必要步骤的假设。特异性目的2：验证成纤维细胞II型细胞通信涉及典型II型细胞ErbB4受体信号通路而不是ErbB4易位到细胞核的假设。特异性目的3：验证雄激素通过转化生长因子β (TGF)通过增加p66Shc蛋白和激活，下调II型细胞成纤维细胞的TACE生成和ErbB4信号传导，延迟表面活性剂合成诱导的假设。这项工作的意义在于对成纤维细胞II型细胞分化控制胎儿肺成熟所涉及的分子事件进行机制理解。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.