HOW DOES ANDROGEN INHIBIT FETAL LUNG MATURATION

描述：(改编自申请者的摘要)这一目标 应用是为了更好地理解 成纤维细胞-II型细胞通讯调控血管生成的研究进展 表面活性剂合成。研究人员已经证明，表皮的生长 因子及其受体(EGFR)控制这种通讯的启动， 而双氢睾酮(DHT)和转化生长因子β(TGFβ) 抑制它。尼尔森博士最近对这其中的元素有了新的见解 过程，表明EGF家族的其他成员对此很重要 进程。他建议确定成纤维细胞II型的分子机制 细胞通讯，包括它们的积极和消极的调节。他 胎肺成纤维细胞中EGFR活化可刺激 激活II型ErbB-2受体的神经调节蛋白(NRG)的产生 刺激细胞合成表面活性物质。此外，DHT和转化生长因子β抑制 这条路。要测试的具体目标是1)机制 成纤维细胞-II型细胞通讯受特异性ErbB受体控制 胎肺成纤维细胞和II型成纤维细胞的表达、二聚化和转运 并确定成纤维细胞中的哪些二聚体诱导 成纤维细胞与II型细胞的通讯，以及II型细胞中的哪些二聚体 刺激表面活性物质合成；2)EGF-R激活正向调节 成纤维细胞通过刺激成纤维细胞产生 NRG，然后诱导表面活性物质的合成。他们将研究 EGF-R激活对NRG产生的上调和抑制作用 NRG生产以测试这是否会移除EGF-R激活的能力 诱导成纤维细胞-II型细胞通讯；3)DHT和TGFβ下调 ErbB受体激活和NRG产生的特异性元件，干扰 成纤维细胞-II型细胞通讯。他们将研究DHT的影响和 转化生长因子β对成纤维细胞和II型ErbB受体表达和激活的影响 细胞对胎肺成纤维细胞产生NRG的影响 II型细胞中表面活性物质的合成。这些研究有望提供 对表面活性物质合成调控机制的重大新认识 胎肺，为开发新的 预防和治疗RDS的策略。

DESCRIPTION: (Adapted from the applicant's abstract) The goal of this application is to develop better understanding of the mechanism of fibroblast-type II cell communication which regulate the development of surfactant synthesis. The investigators have shown that the epidermal growth factor and its receptor (EGFR) control the initiation of this communication, while dihydrotestosterone (DHT) and transforming growth factor beta (TGF beta) inhibit it. Dr. Nielsen has recently gained new insight to the elements of this process, showing that other members of the EGF family are important to this process. He proposes to identify the molecular mechanisms of fibroblast-type II cell communication, including their positive and negative regulation. He hypothesizes that EGFR activation in fetal lung fibroblasts stimulates production of neuregulin (NRG) which activates ErbB-2 receptors on type II cells to stimulate surfactant synthesis. Furthermore, DHT and TGF beta inhibit this pathway. The Specific Aims to be tested are that 1) the mechanisms of fibroblast-type II cell communication are controlled by specific ErbB receptor expression , dimerization and trafficking in fetal lung fibroblasts and type II cells during development and identify which dimers in fibroblasts induce fibroblast-type II cell communication, and which dimers in type II cells stimulate surfactant synthesis; 2) EGF-R activation positively regulates fibroblast-type II cell communication by stimulating fibroblasts to produce NRG, which then induces surfactant synthesis. They will study the effect of upregulation and inhibition of EGF-R activation on NRG production, and inhibit NRG production to test if this removes the ability of EGF-R activation to induce fibroblast-type II cell communication; 3) DHT and TGFbeta down regulate specific elements of ErbB receptor activation and NRG production, disrupting fibroblast-type II cell communication. They will study the effects of DHT and TGFbeta on ErbB receptor expression and activation in fibroblasts and type II cells, on NRG production by fetal lung fibroblasts, and stimulation of surfactant synthesis in type II cells. These studies are expected to provide significant new insights to the mechanisms regulating surfactant synthesis in the fetal lung and make important contributions towards developing new strategies for preventing and treating RDS.