How Does Androgen Inhibit Fetal Maturation

雄激素如何抑制胎儿成熟

基本信息

批准号：
7369822
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
项目类别：
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/7369822
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 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 Newborn Respiratory Distress Syndrome Nuclear Pathway interactions Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide 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 surfactant

项目摘要

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）：尽管产前类固醇和新生儿外源性表面活性剂取得了进步，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，长期以来，II 型成纤维细胞通讯被认为是成熟过程中的重要调节过程。表面活性剂合成的研究进展，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，我们证明了生长因子神经调节蛋白（NRG）（ErbB3 和 ErbB4 受体的配体）的产生。通过胎儿肺成纤维细胞并刺激 II 型细胞表面活性剂合成。在本申请中，我们建议进一步确定控制 II 型成纤维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。我们增强了 ErbB4 与其他 ErbB 受体以异二聚体的形式发挥作用，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 在胎儿肺成纤维细胞中的产生方式以及含有 ErbB4 的二聚体是如何被激活的。我们提出了三个具体目标 1：检验胎儿肺成纤维细胞中 TACE 的激活是必要步骤的假设。具体目标 2：检验 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 易位至细胞核的假设。转化生长因子β（TGF¿ ）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 II 型成纤维细胞中涉及的分子事件形成机制理解。控制胎儿肺成熟的细胞分化将有助于开发预防和治疗 RDS 的新方法。