ANDROGEN INHIBITION OF FETAL LUNG MATURATION

雄激素对胎肺成熟的抑制

• 批准号: 3353866
• 负责人: Heber C. Nielsen
• 金额: $ 19.08万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-07-01 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3353866
• 关键词: androgens; cell biology; cell cell interaction; cell differentiation; density gradient ultracentrifugation; embryo /fetus cell /tissue; epidermal growth factor; fibroblasts; gel electrophoresis; growth factor receptors; hormone regulation /control mechanism; immunoprecipitation; laboratory rat; lung; messenger RNA; northern blottings; phase contrast microscopy; phosphorylation; receptor binding; receptor expression; respiratory distress syndrome of newborn; respiratory epithelium; tissue /cell culture; transforming growth factors; western blottings

Hyaline Membrane Disease (HMD) remains the leading cause of neonatal morbidity and mortality in the premature infant, despite recent therapeutic advances. A better understanding of the molecular mechanisms controlling lung maturation is critical for developing improved strategies to prevent and treat HMD. The main objective of this work is to define the cellular and molecular mechanisms controlling fetal lung differentiation as the lung prepares for surfactant synthesis. Previous work shows that epidermal growth factor (EGF) stimulates the development of cell-cell communications controlling lung maturation; and that androgen inhibits the development of those cell-cell communications. In this proposal it is hypothesized that the interaction of EGF with its receptor (EGF-R) is an important regulatory mechanism in fetal lung differentiation, and that androgen delays the development of this important regulatory mechanism. This hypothesis will be tested by addressing 3 Specific Aims. SA 1: Test the hypothesis that the EGF-R is developmentally regulated, consistent with a role in regulating the fibroblast-type II cell communications controlling fetal lung maturation. SA 2: Test the hypothesis that activation of the EGF-R by EGF regulates fibroblast-type II cell communications in fetal lung maturation. SA 3: Test the hypothesis that the mechanism by which androgen delays fibroblast-type II cell communication controlling lung maturation involves delaying the development of the EGF-R. The development of cell- specific (type II cell, fibroblast) EGF binding, EGF-R levels and EGF-R mRNA will be studied during fetal development, using receptor binding, immunoprecipitation, and Northern blot analysis. Cells deficient in EGF- R's will be replenished with intact, active EGF-R's, and the ability to influence cell-cell communications with EGF will be studied. EGF-R phosphorylation will be interrupted to learn about the importance of phosphorylation in control of lung maturation. The regulation of EGF-R development by hormones (androgen, glucocorticoids) and growth factors (EGF, TGFbeta) will be studied. These studies will further clarify the controls of fetal lung differentiation, and show how positive and negative regulatory controls become integrated to allow the normal progression of development. This will help develop better strategies for prevention of HMD, and will contribute to an improved understanding of control of fetal development.

透明膜病（HMD）仍然是新生儿的主要原因 早产儿的发病率和死亡率，尽管最近 治疗进展。 更好地理解分子机制 控制肺成熟对于发展改进至关重要 预防和治疗 HMD 的策略。 这项工作的主要目标是 定义控制胎儿肺的细胞和分子机制 当肺准备表面活性剂合成时进行分化。 以前的 研究表明表皮生长因子（EGF）可刺激发育 控制肺成熟的细胞间通讯；还有那个 雄激素抑制这些细胞间通讯的发展。 在 该提议假设 EGF 与其相互作用 受体（EGF-R）是胎儿肺的重要调节机制 分化，并且雄激素延迟了这种分化的发展 重要的监管机制。 这个假设将被检验 解决 3 个具体目标。 SA 1：检验 EGF-R 的假设 是发育调节的，与调节作用一致 控制胎儿肺成熟的 II 型成纤维细胞通讯。 SA 2：检验 EGF 激活 EGF-R 调节的假设 胎儿肺成熟过程中成纤维细胞 II 型细胞通讯。 SA 3： 检验雄激素延迟机制的假设 控制肺成熟的 II 型成纤维细胞通讯 涉及延迟 EGF-R 的发育。 细胞的发展- 特异性（II 型细胞、成纤维细胞）EGF 结合、EGF-R 水平和 EGF-R 将在胎儿发育过程中利用受体结合来研究 mRNA， 免疫沉淀和 Northern blot 分析。 细胞缺乏EGF- R 将得到完整、活跃的 EGF-R 的补充，并且能够 将研究 EGF 对细胞间通讯的影响。 表皮生长因子受体 将中断磷酸化以了解磷酸化的重要性 磷酸化控制肺成熟。 EGF-R的调节 激素（雄激素、糖皮质激素）和生长因子的发育 （EGF、TGFbeta）将被研究。 这些研究将进一步阐明 控制胎儿肺分化，并显示如何积极和 负面监管控制变得一体化，以允许正常的 发展的进展。 这将有助于制定更好的策略 预防 HMD，并将有助于加深对 HMD 的了解 控制胎儿发育。