HOW DOES ANDROGEN INHIBIT FETAL LUNG MATURATION

描述：（改编自申请人的摘要） 应用是为了更好地了解 成纤维细胞II型细胞通讯，调节发展， 表面活性剂合成研究人员发现， 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（TGF β） 抑制它。尼尔森博士最近获得了新的见解，这一要素 EGF家族中的其他成员在这一过程中也起着重要作用。 过程他建议确定成纤维细胞II型的分子机制， 细胞通讯，包括其积极和消极的调节。他 假设胎儿肺成纤维细胞中EGFR的激活刺激了 产生神经调节蛋白（NRG），其激活II型ErbB-2受体 细胞刺激表面活性剂的合成。此外，DHT和TGF β抑制 这条路。待测试的具体目的是：1） 成纤维细胞II型细胞通讯由特异性ErbB受体控制 胎儿肺成纤维细胞中的表达、二聚化和运输以及II型 细胞在发育过程中，并确定成纤维细胞中的二聚体诱导 成纤维细胞-II型细胞通讯，并且在II型细胞中二聚体 刺激表面活性剂合成; 2）EGF-R激活正调节 成纤维细胞II型细胞通信通过刺激成纤维细胞产生 NRG，然后诱导表面活性剂合成。他们将研究 上调和抑制EGF-R活化对NRG产生，并抑制 NRG生产，以测试这是否消除了EGF-R活化的能力， 诱导成纤维细胞II型细胞通讯; 3）DHT和TGF β下调 ErbB受体激活和NRG产生的特定元件， 成纤维细胞II型细胞通讯。他们将研究DHT的影响， TGF β对成纤维细胞和II型ErbB受体表达和活化的影响 细胞，对胎儿肺成纤维细胞产生NRG的影响，以及刺激 II型细胞中的表面活性剂合成。预计这些研究将提供 重要的新的见解，调节表面活性剂合成的机制， 胎儿肺，并作出重要贡献，发展新的 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.