Molecular Mechanisms of Lung Branching Morphogenesis

肺分支形态发生的分子机制

• 批准号: 6620389
• 负责人: WEI SHI
• 金额: $ 29.92万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620389
• 关键词: biological signal transduction; bone morphogenetic proteins; developmental genetics; embryo /fetus; embryogenesis; gene expression; genetic regulation; genetic regulatory element; growth factor receptors; histogenesis; immunocytochemistry; immunoprecipitation; in situ hybridization; inhibitor /antagonist; intermolecular interaction; laboratory mouse; lung; lung development; mammalian embryology; mesenchyme; morphometry; northern blottings; phosphorylation; protein structure function; respiratory epithelium; transcription factor; western blottings

Early embryonic lung development, particularly early branching morphogenesis, is controlled by epithelium-mesenchyme interaction, in which autocrine/paracrine growth factors, including BMP4, are involved. This proposal is focused on determining the mechanisms by which BMP4 induces lung branching morphogenesis in mouse. Hypothesis: BMP4 induces mouse embryonic lung epithelial branching morphogenesis in a mesenchyme-dependent manner through activation of specific downstream signaling proteins. Specific Aims: Aim 1. To determine mesenchyme mediated inductive mechanisms of BMP4 on epithelial branching morphogenesis of E11.5 mouse embryonic lung. Aim 2. To define gene expression pattern, specific activation, and biological function of specific BMP4 receptors and downstream Smads during BMP4 induced embryonic lung branching morphogenesis. Aim 3. To determine the biological roles of specific negative regulators (Gremlin, NMA, and Smad6) of BMP4 signaling during embryonic lung branching morphogenesis. Health Relevance: The studies will provide fundamental knowledge about BMP4 and lung development, which will help us to better understand congenital and neonatal pulmonary diseases as well as lung injury repair. This basic information may aid in the future design of novel therapeutic strategies to prevent and treat such serious pulmonary diseases as lung hypoplasia, bronchopulmonary dysplasia and emphysema.

早期胚胎肺发育，特别是早期分支形态发生，受上皮-间充质相互作用的控制，自分泌/旁分泌生长因子，包括BMP4，参与其中。本研究的重点是确定BMP4诱导小鼠肺分支形态发生的机制。假设：BMP4通过激活特定的下游信号蛋白，以间充质依赖的方式诱导小鼠胚胎肺上皮分支形态发生。目的：1.探讨BMP4对E11.5小鼠胚肺上皮分支形态发生的诱导机制。目的2.明确BMP4诱导的胚胎肺分支形态发生过程中BMP4受体及其下游Smads的基因表达模式、特异性激活及其生物学功能。目的3.探讨BMP4信号的特异性负调控因子(Gremlin、NMA和Smad6)在胚胎肺分支形态发生中的生物学作用。健康相关性：这些研究将提供关于BMP4和肺发育的基础知识，这将有助于我们更好地了解先天性和新生儿肺部疾病以及肺损伤的修复。这些基本信息可能有助于未来设计新的治疗策略来预防和治疗严重的肺部疾病，如肺发育不良、支气管肺发育不良和肺气肿。