ANDROGEN INHIBITION OF FETAL LUNG MATURATION

该项目的主要目标是更好地定义机制 控制胎儿肺的成熟。这将通过以下方式实现 继续研究计时性别差异的机制 关于胎儿肺发育的问题，涉及四个具体目标。具体目标编号 1是进一步刻画调节生产的机制 胎肺成纤维细胞表达成纤维细胞肺泡细胞因子。鼠标 将使用睾丸女性化模型(TFM小鼠)。将会研究 性别差异在男性、女性和女性中的表达 以及雄激素不敏感的男性胎儿，通过确定激素或 外源生长因子，如表皮生长因子(EGF)， 血小板衍生生长因子(PDGF)或生长抑素C刺激 原料粉的生产。第二个具体目标是研究由 胎肺调节其生长和分化。.的存在 不同发育阶段的不同因素依次 调节生长和分化可能解释了性是如何 表面活性剂的合成出现了差异。Fpf有条件的介质来自 将对TFM小鼠进行研究，以确定FPF活性是否缺乏 雄性与促进生长的活动相吻合。性别化器官培养 将在进一步的实验中用于制备胎兔肺 胎肺成熟早期和晚期的条件培养液。 这种有条件的媒体将接受促进生长和 雄性和雌性的分化活性。第三个具体目标是 研究内源性生长因子表达的调控机制 肺中的因素。内源性激素效应的激素调节作用 或外源性生长因子(EGF、PDGF、生长抑素-C)将被研究。 具体目标4是开始描述增长和 胎肺分化因子在特定条件下的鉴定 目的2.条件培养液将通过高效液相色谱和凝胶柱进行分级 来分离活性组分。将启动研究以分离出 参与的特定蛋白质，并开始表征它们。这个 从这些研究中获得的信息将有助于设计 预防早产儿肺透明膜病的策略。是这样的 战略必须牢固地建立在对胎儿肺事件的了解基础上 需要在男性和女性身上加强的发育。此外 这些研究将为我们的总体理解提供有价值的见解。 生物钟调节发育事件的时间。

The main objective of this project is to better define the mechanisms controlling maturation of the fetal lung. This will be accomplished by continuing the study of the mechanisms of the sex difference in the timing of fetal lung development, addressing four specific aims. Specific Aim No. 1 is to further characterize the mechanism regulating the production of fibroblast pneumonocyte factor (FPF) by fetal lung fibroblasts. The mouse model of testicular feminization (Tfm mouse) will be used. Will study the mechanism of the sex difference in the expression of FPF in male, female, and androgen-insensitive male fetuses, by determining whether hormones or exogenous growth factors such as epidermal growth factor (EGF), platlet-derived growth factor (PDGF) or somatomedin C stimulate the production of FPF. Specific Aim No. 2 is to study the factors produced by the fetal lung to regulate its growth and differentiation. The presence of different factors at different developmental stages which sequentially regulate growth and differentiation is a likely explanation of how sex differences in surfactant synthesis arise. FPF conditioned media from the Tfm mouse will be studied to identify whether the lack of FPF activity in males coincides with growth-promoting activity. Sex-specific organ culture of fetal rabbit lung will be used in further experiments to prepare conditioned media from early and late stages in fetal lung maturation. This conditioned media will be tested for growth-promoting and differentiation activity in males and females. Specific Aim No. 3 is to study the mechanisms which regulate the expression of endogenous growth factors in the lung. The hormonal mediation of the effects of endogenous or exogenous growth factors (EGF, PDGF, somatomedin-C) will be studied. Specific Aim No. 4 is to begin to characterize the growth and differentiation factors made by the fetal lung as identified in Specific Aim No. 2. Conditioned media will be fractionated by HPLC and gel columns to isolate the active fractions. Studies will be initiated to isolate the specific proteins involved and to begin to characterize them. The information gained from these studies will be useful for devising strategies to prevent hyaline membrane disease in premature infants. Such strategies must be firmly based on a knowledge of the events in fetal lung development which need to be enhanced in male and in females. In addition these studies will provide valuable insights into the general understanding of the biological clock which regulates the timing of developmental events.