ANDROGEN INHIBITION OF FETAL LUNG MATURATION

肺透明膜病（HMD）仍然是新生儿肺透明膜病的主要原因。 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善的 预防和治疗HMD的策略。 这项工作的主要目标是 确定控制胎儿肺的细胞和分子机制 分化作为肺表面活性剂合成的准备。 先前 研究表明，表皮生长因子（EGF）刺激发育， 控制肺成熟的细胞间通讯; 雄激素抑制这些细胞间通讯的发展。 在 这一建议，它是假设，EGF的相互作用， EGF-R受体是胎肺重要的调节机制 分化，而雄激素延迟了这种分化的发展。 重要的监管机制。 这一假设将由以下人员进行检验： 三个具体目标。 SA 1：检验EGF-R 是发育调节的，与调节 成纤维细胞II型细胞通信控制胎儿肺成熟。 SA 2：测试EGF激活EGF-R调节 成纤维细胞II型细胞通信在胎肺成熟。 SA 3： 检验雄激素延缓衰老的机制 成纤维细胞II型细胞通讯控制肺成熟 包括延迟EGF-R的发展。 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 mRNA将在胎儿发育过程中进行研究，使用受体结合， 免疫沉淀和北方印迹分析。 缺乏EGF的细胞 R的将补充完整的，活性EGF-R的，和能力， 研究EGF对细胞间通讯的影响。 EGF-R 磷酸化将被中断，以了解 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，TGF β）进行研究。 这些研究将进一步阐明 胎儿肺分化的控制，并显示如何积极和 负面监管控制成为一体，以允许正常的 发展的进程。 这将有助于制定更好的战略， 预防HMD，并将有助于更好地了解 控制胎儿发育。

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.