ANDROGEN INHIBITION OF FETAL LUNG MATURATION

肺透明膜病(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 治疗方面的进展。更好地理解分子机制 控制肺成熟是改善病情发展的关键 预防和治疗HMD的策略。这项工作的主要目标是 明确控制胎肺的细胞和分子机制 分化为肺为合成表面活性物质做准备。上一首 研究表明，表皮生长因子(EGF)促进发育 控制肺成熟的细胞-细胞通讯； 雄激素抑制这些细胞间通讯的发展。在……里面 这一提议假设EGF与其自身的相互作用 受体(EGF-R)是胎肺的重要调节机制 分化，而雄激素延缓了这一过程的发展 重要的监管机制。这一假设将通过以下方式检验 解决3个具体目标。SA 1：测试EGF-R的假设 是发育调节的，与调节 成纤维细胞-II型细胞通讯控制胎肺成熟。 SA 2：验证EGF激活EGF-R调节的假设 胎肺成熟过程中成纤维细胞与II型细胞的通讯。SA 3： 验证这样一种假设，即雄激素延迟的机制 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 在胎儿发育期间，将使用受体结合的方法来研究mRNA， 免疫沉淀和Northern印迹分析。缺乏EGF的细胞- R将补充完整、活性的EGF-R，并能够 将研究EGF对细胞间通讯的影响。EGF-R 磷酸化将被中断，以了解 磷酸化在控制肺成熟中的作用。表皮生长因子受体的调控 激素(雄激素、糖皮质激素)和生长因子的发育 (EGF，TGFbeta)将被研究。这些研究将进一步澄清 控制胎儿肺的分化，并显示出如何阳性和 负面监管控制变得综合起来，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.