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: 6526592
• 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 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6526592
• 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; 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.达曼医学博士目前是新英格兰医学中心新生儿医学部的研究和临床研究员，以及贝斯以色列医院信号转导部的研究员。她正在申请这个奖项，以发展作为一个独立的科学家在新生儿与她的研究专注于胎儿肺发育的职业生涯。她将在两位导师Nielsen博士和Cantley博士的帮助下实现这一目标。肺表面活性物质由磷脂和脱辅基蛋白组成，对肺成熟至关重要。胎儿肺发育过程中表面活性物质缺乏导致新生儿窘迫综合征。成纤维细胞-肺细胞-因子（FPF）是成纤维细胞衍生的多肽分化因子，其调节肺II型上皮细胞中的表面活性剂合成。我们有强有力的证据表明，Neuregulin-1（NRG 1），一种基质衍生的生长因子，以前参与乳腺上皮细胞的成熟，是FPF的关键组成部分。对于我们的初步研究，我们使用了MLE 12细胞，其显示胎儿II型细胞的特征。我们现在建议进一步调查的作用，NRG及其受体调节肺发育过程中的表面活性物质的合成使用原代胎鼠细胞。这项建议的具体目标有三个方面。首先，将确定NRG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。其次，将研究肺发育期间NRG表达/产生的调节。第三，erbB受体和细胞内配体中的哪一个参与间充质-II型细胞通信中的NRG信号通路的问题将被研究。目的是进一步了解表面活性剂合成的调节。这将有助于制定诊断和治疗策略，减少早产儿急性和慢性肺部疾病的负担。