Lung epithelial and vascular morphogenesis

描述(由申请人提供)： 肺血管的共形态发生在与上皮的正确位置对于最终过渡到空气呼吸是必不可少的，在致死性的人类肺发育不良和新生儿肺损伤中会受到不利的影响。到目前为止，推动这一协调进程的机制还不完全清楚。零突变表明FGF10信号是肺上皮形态发生所必需的。目前，我们已发表的初步研究结果表明，血管内皮生长因子信号可促进血管和上皮的形态发生。然而，VEGFR2在胚胎间充质中表达，而不是在上皮细胞中表达，提示间接刺激上皮细胞。假设：成纤维细胞生长因子和血管内皮生长因子信号在功能上共同调节肺上皮细胞和血管的形态发生。目的1.研究胚胎肺形态发生过程中FGF10和血管内皮生长因子信号通路中的关键元件之间的精确时空关系。目的2.采用新的可诱导和可逆的小鼠肺功能获得和丧失模型，在体内确定血管内皮生长因子信号对肺上皮细胞和血管形态发生的功能影响。目的3.探讨成纤维细胞生长因子10(FGF10)信号在肺上皮和血管形态发生中调节血管内皮生长因子(VEGF)信号的作用。目的4.在无血清、化学定义的胚胎肺器官培养系统中，确定和比较关键的FGF10和血管内皮生长因子信号转导元件的功能作用，以及血管内皮生长因子对肺上皮细胞的作用是直接的还是间接的。

DESCRIPTION (provided by applicant): Co-morphogenesis of the lung vasculature in correct apposition to the epithelium is essential for the eventual transition to air breathing and is adversely impacted in lethal forms of human lung hypoplasia and neonatal lung injury. As yet the mechanisms that drive this coordinated process are incompletely understood. Null mutation reveals that FGF10 signaling is absolutely required for epithelial morphogenesis in the lung. Now our published and preliminary results show that VEGF signaling enhances both vascular and epithelial morphogenesis. However VEGFR2 is expressed in the embryonic mesenchyme and not the epithelium, suggesting indirect stimulation of the epithelium. Hypothesis: FGF and VEGF signaling functionally co-regulate lung epithelial and vascular morphogenesis. Aim 1. To determine the precise temporospatial relationship between the key elements in the FGF10 and VEGF signaling pathways during embryonic lung morphogenesis. Aim 2. To determine the functional impact of VEGF signaling on lung epithelial and vascular morphogenesis in vivo using novel inducible and reversible gain and loss of function in mice. Aim 3. To determine the function of FGF10 signaling to regulate VEGF signaling during lung epithelial and vascular morphogenesis in vivo. Aim 4. To determine and compare the functional role of key FGF10 and VEGF signaling elements and to determine whether the effects of VEGF on the epithelium are direct or indirect in serumless, chemically defined embryonic lung organ culture system.