How Does Androgen Inhibit Fetal Maturation

描述（由申请方提供）：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治疗取得了进展，但在美国仍是婴儿死亡率的主要原因。需要对控制胎儿肺成熟的机制有更好的理解，以开发新的改进的治疗方法来预防和/或治疗RDS。成纤维细胞II型细胞通信长期以来一直被认为是一个重要的调节过程中成熟的表面活性剂的合成，但只有在过去的几年中取得了进展，在破译这种通信的机制。在上一个资助期，我们发现生长因子Neuregulin（NRG）是ErbB 3和ErbB 4受体的配体，由胎肺成纤维细胞产生，并刺激II型细胞表面活性剂的合成。在本申请中，我们提出进一步确定控制成纤维细胞II型细胞通信的分子机制，并了解这些机制是如何被正向和负向调节的。我们假设ErbB 4与其他ErbB受体以异二聚体形式起作用，控制成纤维细胞II型细胞通讯和表面活性剂合成。为了验证这一点，我们将重点研究NRG是如何在胎肺成纤维细胞中产生的，含ErbB 4的二聚体是如何被激活的，以及雄激素是如何干扰这一信号传导过程的。我们提出三个具体目标。具体目的1：检验以下假设：在胎肺成纤维细胞中激活TACE是成纤维细胞II型通讯的必要步骤。具体目标二：检验成纤维细胞-II型细胞通信涉及典型的II型细胞ErbB 4受体信号通路，而不是ErbB 4易位到细胞核的假设。具体目标3：检验雄激素通过转化生长因子β（TGF？）发挥作用，通过增加p66 Shc蛋白和激活、下调成纤维细胞的TACE产生和II型细胞中的ErbB 4信号传导来延迟表面活性剂合成的诱导的假设。这项工作的意义在于开发一个机制的理解成纤维细胞II型细胞分化控制胎肺成熟的分子事件。这样的理解将允许开发新的方法来预防和治疗RDS。

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.