Vasculature is a determinant of epithelial morphogenesis

描述（由申请人提供）： 新生血管是胎儿生长发育的重要调控过程。该过程中的改变可导致在肺发育不良（如支气管肺发育不良（BPD））中发现的伴随血管和组织异常。虽然存在大量关于发育不良性肺病的病理进展的信息，但关于调节其形成的分子机制知之甚少。本建议的目的是确定血管系统是否是正常远端肺形态发生的决定因素。根据我们以前的发现，我们最适合确定调节这种关系的因素：1）抗血管生成蛋白内皮-单核细胞激活多肽（EMAP）II是发育中的肺中的新血管形成的指示剂，因为其表达与血管形成的时期负相关，2）在肺发育的鼠同种异体移植模型中引入重组EMAP II深刻地破坏肺泡毛细血管生长，3）我们的胎肺同种异体移植物模型可以在没有胎盘屏障的情况下检查新生血管和形态发生的关系，4）EphrinB 2 taulacZ和EphB 4 taulacZ转基因小鼠可以指定动脉与静脉血管系统，和5）来自TIE 2gfp转基因小鼠的胎肺内皮细胞容易分离。我们选择了四种策略来识别受新血管形成调节的远端肺形态发生的基本成分，但也可能是血管生成的潜在调节因子：1）跟踪与肺发育相关的动脉和静脉进展，2）表征在整个肺发育过程中由胎儿肺内皮发送的信号，3）确定上皮分化对新血管形成的影响，和4）检查脉管系统对上皮间充质结构组织的贡献。因此，确定负责协调血管形成和远端肺形态发生的因素将提供深入了解其平衡影响肺发育的决定因素。

DESCRIPTION (provided by applicant): Neovascularization is a key regulatory process in fetal growth and development. Alterations within this process can lead to concomitant vascular and tissue abnormalities identified within lung dysplasia such as Bronchopulmonary Dysplasia (BPD). Although a significant amount of information exist regarding the pathologic progression of dysplastic lung diseases, little is known regarding the molecular mechanisms that regulate their formation. The goal of this proposal is to establish, whether the vasculature is a determinant of normal distal lung morphogenesis. We are optimally suited to determine the factors regulating this relationship based on our previous findings that: 1) the anti-angiogenic protein Endothelial-Monocyte Activating Polypeptide (EMAP) II is a director of neovascularization in the developing lung as its expression is inversely correlated to periods of vascularization, 2) introduction of recombinant EMAP II in a murine allograft model of lung development profoundly disrupts alveolar-capillary growth, 3) our fetal lung allograft model can examine neovascular and morphogenic relationships without placental barriers, 4) EphrinB2taulacZ and EphB4taulacZ transgenic mice can designate arterial versus venous vascular systems, and 5) fetal lung endothelial cells from TIE2gfp transgenic mice are readily isolated. We chose four strategies to identify the fundamental components of distal lung morphogenesis regulated by neovascularization, but may also be potential regulators of angiogenesis: 1) track arterial and venous progression in relationship to lung development, 2) characterize the signals sent by the fetal lung endothelium throughout lung development, 3) determine the impact that epithelial differentiation has on neovascularization, and 4) examine the contribution of the vasculature to epithelial mesenchymal structural organization. Thus, identifying the factors responsible for coordinating vascular formation and distal lung morphogenesis will provide insight into the determinants by which their balance can affect lung development.