MYC ONCOGENES IN FETAL LUNG GROWTH AND MATURATION

该项目的总体目标是确定分子和 调节胎儿肺生长和成熟的细胞机制。 先前的研究表明，myc家族原癌基因发挥着关键作用 细胞生长和分化的调节作用。 我们自己和其他人的初步数据表明，表达 发育中的肺中的 c-myc 在接近发病时下调 表面活性剂合成。我们将利用性别差异 肺成熟时间以确定 myc 家族基因的作用 表达控制胎儿肺发育。为了完成我们的 目标 将解决四个具体目标。 具体目标 #1 解决胎儿 myc 癌基因的个体发育 肺。实验将确定c-myc表达的时间过程， 胎鼠、小鼠和兔肺中的 N-myc 和 L-myc 与 表面活性剂合成的发展原位杂交将确定 表达 myc 的细胞类型。 具体目标#2解决了控制表达的机制 myc 在胎儿肺中。激素（皮质醇、雌激素、雄激素和 甲状腺）和生长因子（EGF、TGFBeta 和血小板衍生生长因子） 因子（PDGF）和干扰素）将用于器官培养和 培养肺成纤维细胞和 II 型细胞以确定 myc 表达受到调节以及 myc 表达的变化如何相关 随着肺成纤维细胞和 II 型细胞的成熟开始。 在具体目标#3中，携带myc家族原型的逆转录病毒载体 癌基因将用于确定组成型 myc 的影响 表达对肺成纤维细胞和II型细胞成熟的影响 文化。 在具体目标#4中，myc表达载体将被引入 转基因小鼠以确定组成型myc基因的影响 体内肺发育的表达。 这些实验的结果将有助于更好地理解 胎儿肺部发育的机制。这样的理解 对于制定预防和治疗透明膜的策略至关重要 新生儿疾病。

The overall Objective of this project is to determine the molecular and cellular mechanisms that regulate fetal lung growth and maturation. Previous studies have shown that myc family proto-oncogenes play a key role in the regulation of cellular growth and differentiation. Preliminary data of ourselves and other indicate that the expression of c-myc in the developing lung is down-regulated near the time of onset of surfactant synthesis. We will take advantage of sex differences in the timing of lung maturation to determine the role of myc family gene expression in controlling fetal lung development. To accomplish our objectives four Specific Aims will be addressed. Specific Aim #1 addresses the ontogeny of myc oncogenes in the fetal lung. Experiments will determine the time course of expression of c-myc, N-myc and L-myc in fetal rat, mouse, and rabbit lung in relation to the development of surfactant synthesis. In situ hybridization will determine the cell types expressing myc. Specific Aim #2 addresses the mechanisms controlling the expression of myc in the fetal lung. Hormones (cortisol, estrogen, androgen, and thyroid), and growth factors (EGF,TGFBeta, and platelet-derived growth factor (PDGF), and interferon) will be used in organ culture and in cultured lung fibroblasts and type II cells to determine how myc expression is regulated and how changes of myc expression are correlated with the onset of maturation of the lung fibroblast and type II cell. In Specific Aim #3, retroviral vectors harboring myc family proto- oncogenes will be used to determine the effects of constitutive myc expression on the maturation of lung fibroblasts and type II cells in culture. In Specific Aim #4, myc expression vectors will be introduced into transgenic mice to determine the effects of constitutive myc gene expression on the development of the lung in vivo. The results of these experiments will lead to a better understanding of the mechanisms underlying fetal lung development. Such an understanding is crucial to developing strategies to prevent and treat Hyaline Membrane Disease of the newborn.