MYC ONCOGENES IN FETAL LUNG GROWTH AND MATURATION

胎儿肺生长和成熟中的 MYC 癌基因

• 批准号: 3362074
• 负责人: Heber C. Nielsen
• 金额: $ 27.48万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 1992-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3362074
• 关键词: Retroviridae; cell differentiation; embryo /fetus; embryo /fetus culture; fibroblasts; gender difference; gene expression; genetically modified animals; growth /development; growth factor; hormone regulation /control mechanism; in situ hybridization; laboratory mouse; laboratory rabbit; laboratory rat; lung; mammalian embryology; organ culture; protooncogene; pulmonary surfactants; transposon /insertion element

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.

这个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， C-myc在肺发育中的表达在发病时下调。 表面活性剂合成。我们将利用性别差异在 肺成熟时间决定myc家族基因的作用 在控制胎肺发育中的表达。为了实现我们的目标 目标将涉及四个具体目标。 具体目标#1解决胎儿myc癌基因的个体发育 阿龙。实验将确定c-myc表达的时间进程， N-myc和L-myc在胎鼠、小鼠和兔肺中的表达及其与血管生成的关系 表面活性剂合成研究进展。原位杂交将确定 表达myc的细胞类型。 具体目标#2解决了控制基因表达的机制 胎肺中的MYC。激素(皮质醇、雌激素、雄激素和 甲状腺)和生长因子(EGF、TGFβ和血小板衍生生长 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 Myc基因的表达受调控以及myc基因表达的变化是如何相互关联的 随着肺成纤维细胞和II型细胞成熟的开始。 在特定的目标#3中，携带myc家族原的逆转录病毒载体- 癌基因将被用来确定结构性myc的影响。 肺成纤维细胞和II型细胞成熟过程中的表达 文化。 在特定的目标#4中，myc表达载体将被引入 转基因小鼠检测组成型myc基因的作用 在体内表达对肺发育的影响。 这些实验的结果将使我们更好地理解 胎儿肺发育的机制。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。