NEUREGULINS AND THEIR RECEPTORS IN LUNG DEVELOPMENT

肺发育中的神经调节蛋白及其受体

• 批准号: 6780843
• 负责人: CHRISTIANE E DAMMANN
• 金额: $ 12.83万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6780843
• 关键词: SDS polyacrylamide gel electrophoresis; animal tissue; biological signal transduction; cell cell interaction; cell growth regulation; cell proliferation; embryo /fetus tissue /cell culture; enzyme linked immunosorbent assay; fibroblasts; growth factor receptors; immunocytochemistry; immunoprecipitation; laboratory mouse; lipid biosynthesis; lung development; mesenchyme; organ culture; polymerase chain reaction; pulmonary surfactants; respiratory epithelium; scintillation counter; thin layer chromatography; western blottings

Christiane E.L. Dammann, M.D. is currently a research and clinical fellow in the Division of Newborn Medicine at New England Medical Center and a research fellow in the Division of Signal Transduction at the Beth Israel Hospital. She is applying for this award to develop a career as an independent scientist in Neonatology with her research focused on fetal lung development. She will accomplish this goal with the help of her two mentors Dr. Nielsen and Dr. Cantley. Pulmonary surfactant consists of phospholipids and apoproteins and is critical for lung maturation. Surfactant deficiency during fetal lung development contributes to neonatal distress syndrome. Fibroblast- Pneumocyte-Factor (FPF) is a fibroblast derived polypeptide differentiation factor that regulates surfactant synthesis in lung type II epithelial cells. We have strong evidence that Neuregulin-1 (NRG1), a stromal-derived growth factor previously implicated in mammary gland epithelial cell maturation, is a critical component of FPF. For our preliminary studies we have used MLE 12 cells, which display characteristics of fetal type II cells. We now propose to investigate further the role of NRGs and their receptors in regulating surfactant synthesis during lung development using primary fetal mouse cells. The specific aims of this proposal are threefold. First, the role of the NRGs in the regulation of fibroblast-type II cell communication leading to surfactant synthesis will be determined. Second the regulation of NRG expression / production during lung development will be investigated. Third, the question which of the erbB receptors and intracellular ligands are involved in the NRG signaling pathway in mesenchymal-type II cell communication will be studied. The goal is to gain further insight into the regulation of surfactant synthesis. This should contribute to the development of diagnostic and therapeutic strategies that reduce the burden of acute and chronic lung disease among preterm infants.

Christiane E.L. Dammann，医学博士，目前是新英格兰医学中心新生儿医学部门的研究和临床研究员，也是贝斯以色列医院信号转导部门的研究员。她申请这个奖项是为了发展自己的职业生涯，成为一名独立的新生儿科学家，她的研究重点是胎儿肺发育。她将在她的两位导师尼尔森博士和坎特利博士的帮助下完成这一目标。肺表面活性剂由磷脂和载脂蛋白组成，对肺成熟至关重要。胎儿肺发育过程中表面活性物质缺乏会导致新生儿窘迫综合征。成纤维细胞-肺细胞因子（FPF）是一种源自成纤维细胞的多肽分化因子，调节肺II型上皮细胞中表面活性剂的合成。我们有强有力的证据表明，神经调节蛋白-1 （NRG1）是一种基质来源的生长因子，以前与乳腺上皮细胞成熟有关，是FPF的关键组成部分。在我们的初步研究中，我们使用了MLE 12细胞，它显示了胎儿II型细胞的特征。我们现在打算利用原代胎鼠细胞进一步研究NRGs及其受体在肺发育过程中调节表面活性剂合成中的作用。这项建议的具体目标有三个方面。首先，NRGs在调节成纤维细胞II型细胞通讯导致表面活性剂合成中的作用将被确定。其次，我们将研究NRG在肺发育过程中的表达/产生调控。第三，研究在间充质II型细胞通讯中，erbB受体和细胞内配体哪些参与了NRG信号通路。目标是进一步深入了解表面活性剂合成的调控。这应有助于制定诊断和治疗策略，减轻早产儿急性和慢性肺病的负担。