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关键调控过程。这一过程中的改变可导致伴随的血管和组织异常，可在肺发育不良中发现，如支气管肺发育不良(BPD)。虽然有大量关于发育不良肺部疾病的病理进展的信息，但对调节其形成的分子机制知之甚少。这项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。我们最适合确定这种关系的调节因素，因为我们以前的发现：1)抗血管生成蛋白内皮单核细胞激活多肽(EMAP)II是发育中肺血管生成的导向器，因为其表达与血管形成时间呈负相关；2)将重组EMAP II引入小鼠肺发育的同种异体移植模型，严重干扰了肺泡-毛细血管的生长；3)我们的胎肺移植模型能够在没有胎盘屏障的情况下观察新生血管和形态发生的关系；4)EPhinB2taulacZ和EphB4taulacZ转基因小鼠可以指定动脉和静脉系统；5)来自TIE2gp转基因小鼠的胚胎肺内皮细胞很容易分离。我们选择了四种策略来确定受新生血管调控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素：1)跟踪与肺发育相关的动脉和静脉进程，2)表征胎儿肺内皮细胞在整个肺发育过程中发出的信号，3)确定上皮细胞分化对新生血管的影响，以及4)检查血管系统对上皮间充质结构组织的贡献。因此，识别负责协调血管形成和远端肺形态发生的因素将有助于深入了解它们的平衡可以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.