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: 6323560
• 负责人: CHRISTIANE E DAMMANN
• 金额: $ 13.55万
• 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 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6323560
• 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; 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.

克里斯蒂安·E·L·达曼医学博士目前是新英格兰医学中心新生医学部的研究和临床研究员，也是贝丝以色列医院信号传导部的研究员。她正在申请这一奖项，以发展她在新生儿学领域的独立科学家的职业生涯，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实现这一目标。肺表面活性物质由磷脂和载脂蛋白组成，对肺成熟至关重要。胎儿肺发育过程中肺表面活性物质缺乏可导致新生儿窘迫综合征。肺成纤维细胞因子是一种成纤维细胞来源的多肽分化因子，调节肺II型上皮细胞表面活性物质的合成。我们有强有力的证据表明，神经调节蛋白-1(NRG1)，一种先前与乳腺上皮细胞成熟有关的间质来源的生长因子，是FPF的关键成分。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。我们现在建议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物质合成的作用。这项提议的具体目标有三个。首先，将确定NRGs在调节成纤维细胞-II型细胞通讯导致表面活性物质合成中的作用。其次，将研究NRG在肺发育过程中的表达/产生的调节。第三，将研究在NRG信号通路中，哪些erb B受体和细胞内配体参与了间充质-II型细胞通讯。其目的是进一步了解表面活性物质合成的调控。这应有助于制订诊断和治疗战略，减轻早产儿急性和慢性肺部疾病的负担。