How Does Androgen Inhibit Fetal Maturation

雄激素如何抑制胎儿成熟

• 批准号: 7571632
• 负责人: Heber C. Nielsen
• 金额: $ 40.3万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-20 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7571632
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Androgens; Binding; Cell Communication; Cell Differentiation process; Cell Nucleus; Cells; Communication; Complex; Conditioned Culture Media; Development; Down-Regulation; ERBB2 gene; Enzymes; Epidermal Growth Factor Receptor; ErbB4 gene; Event; Fetal Lung; Fibroblasts; Funding; Goals; Growth Factor; Infant Mortality; Knock-out; Learning; Ligands; Lung; Membrane; Mitogen-Activated Protein Kinases; Molecular; Morbidity - disease rate; Neonatal; Neuregulins; Nuclear; Pathway interactions; Phospholipids; Phosphorylation; Premature Infant; Process; Production; Protein Isoforms; Proteins; Receptor Activation; Receptor Signaling; Regulation; Relative (related person); Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Steroids; Testing; Time; Transfection; Transforming Growth Factor beta; Transgenic Mice; Translating; Type II Epithelial Receptor Cell; Work; cell type; computerized data processing; dimer; enzyme activity; fetal; improved; lung maturation; mortality; mutant; neonate; novel; novel strategies; p66(ShcA) protein; paracrine; phospholipase C gamma; prenatal; prevent; protein activation; receptor; respiratory distress syndrome; surfactant

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.

描述（由申请人提供）：新生儿呼吸窘迫综合征（RDS）是早产儿发病和死亡的主要原因，并且尽管产前类固醇和新生儿外源性表面活性剂替代品取得了进步，但仍然是美国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。 II 型成纤维细胞通讯长期以来被认为是表面活性剂合成成熟过程中的重要调节过程，但直到最近几年，在破译这种通讯机制方面才取得了进展。在之前的资助期间，我们表明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 型细胞表面活性剂的合成。在此应用中，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，并了解这些机制如何受到正向和负向调节。我们假设 ErbB4 与其他 ErbB 受体形成异二聚体，控制 II 型成纤维细胞通讯和表面活性剂合成。为了测试这一点，我们将重点确定 NRG 如何在胎儿肺成纤维细胞中产生、如何激活包含 ErbB4 的二聚体以及雄激素如何发挥作用来中断此信号传导过程。我们提出三个具体目标。具体目标 1：检验胎肺成纤维细胞中 TACE 的激活是 II 型成纤维细胞通讯的必要步骤这一假设。具体目标 2：检验以下假设：II 型成纤维细胞通讯涉及典型 II 型细胞 ErbB4 受体信号通路，而不是 ErbB4 易位至细胞核。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 p66Shc 蛋白和激活、下调 II 型细胞中成纤维细胞的 TACE 产生和 ErbB4 信号传导来延迟表面活性剂合成的诱导。这项工作的意义在于对控制胎儿肺成熟的 II 型成纤维细胞分化所涉及的分子事件形成机制理解。这种理解将有助于开发预防和治疗 RDS 的新方法。