MYC ONCOGENES IN FETAL LUNG GROWTH AND MATURATION

本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家族的原癌基因起着关键作用 在调节细胞生长和分化中的作用。 我们和其他人的初步数据表明， 在肺发育过程中，c-myc在肺发育过程中的表达在肺发育过程中， 表面活性剂合成我们将利用性别差异， 肺成熟的时间以确定myc家族基因的作用 表达调控胎儿肺发育。完成我们 四个具体目标将得到实现。 具体目标#1解决胎儿中myc癌基因的个体发生 肺。实验将确定c-myc表达的时间过程， N-myc和L-myc在胎鼠、小鼠和兔肺中的表达与肺纤维化的关系 表面活性剂合成的进展。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在胎儿肺中的表达。激素（皮质醇、雌激素、雄激素和 甲状腺）和生长因子（EGF、TGF β和血小板源性生长因子 因子（PDGF）和干扰素）将用于器官培养和 培养的肺成纤维细胞和II型细胞，以确定myc 以及myc表达的变化如何与 随着肺成纤维细胞和II型细胞成熟的开始。 在具体目标#3中，携带myc家族原核表达的逆转录病毒载体， 癌基因将用于确定组成型myc 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表达载体将被引入到 转基因小鼠，以确定组成型myc基因的作用 表达对体内肺发育的影响。 这些实验的结果将使我们更好地了解 胎儿肺发育的机制。这样的理解 对于制定预防和治疗肺透明膜的策略至关重要 新生儿的疾病。

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.