Molecular Mechanisms of Lung Branching Morphogenesis

早期胚胎肺发育，特别是早期分支形态形成，受上皮-间质相互作用控制，其中自分泌/旁分泌生长因子，包括BMP4，参与其中。本研究旨在探讨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，以间质依赖的方式诱导小鼠胚胎肺上皮分支形态发生。具体目标：目标1。探讨间质介导的BMP4诱导E11.5小鼠胚胎肺上皮分支形态发生的机制。目标2。目的：明确BMP4诱导的胚胎肺分支形态发生过程中，BMP4特异性受体和下游Smads的基因表达模式、特异性激活和生物学功能。目标3。确定BMP4信号的特异性负调节因子（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：这些研究将提供有关BMP4与肺发育的基础知识，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修复。这些基本信息可能有助于未来设计新的治疗策略，以预防和治疗肺发育不全、支气管肺发育不良和肺气肿等严重肺部疾病。

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.