The Gene Expression Program of Mouse Lung Development

描述（由申请人提供）： 肺是由两个互锁的分支网络的管道，气道和肺血管，汇聚在肺泡血液再氧合。这些网络的结构缺陷或它们的关联可能导致或促成严重的肺部疾病，但关于这些复杂的分支结构如何在发育过程中出现或它们的结构如何协调，我们知之甚少。肺开始发育为一对气管（支气管），由原始的血管网络包围。随后，数以百万计的气道分支沿着与类似数量的动脉和静脉一起发芽。已经鉴定了在初始气道分支事件中起作用的少量基因和信号通路，但是在人类、小鼠或其他动物中控制肺血管发育并使其发育与气道发育协调的遗传程序尚未阐明。这项资助的长期目标是阐明控制肺血管形成和分支的遗传程序，并协调它们与气道的发育。具体目标是：（1）确定肺血管发育中分支事件的模式和细胞机制及其与发育中小鼠肺中气道和其他肺组织的关系和依赖性;（2）为了在发育中的小鼠肺中在全基因组尺度上绘制基因表达的空间模式，包括分析它们的相对表达模式和这些模式与目标1中定义的形态学和细胞事件的关系。所分析的基因将包括所有已知的信号分子、受体和由信号通路诱导的基因，以及与血管发育有关的基因;（3）建立在胚胎小鼠肺中高度定位的区域和不同位置错误表达和失活肺发育基因的方法，并使用该方法来评估可能涉及血管和气道发育协调的两个基因的功能。

DESCRIPTION (provided by applicant): The lung is composed of two interlocking branched networks of tubes, the airways and pulmonary blood vessels, which converge in the alveoli where blood is reoxygenated. Defects in the structure of these networks or their association can cause or contribute to serious pulmonary disease, but very little is known about how these complex branched structures arise during development or how their structures are coordinated. The lung begins development as a pair of air tubes (bronchi) which are surrounded by a primitive network of blood vessels. Subsequently, millions of airway branches sprout along with a similar number of arteries and veins. A small number of genes and signaling pathways that function in the initial airway branching events have been identified, but the genetic programs that control pulmonary vascular development and coordinate its development with that of the airways have not been elucidated in the humans, mouse, or other animals. The long term goal of this grant is to elucidate the genetic program that controls the formation and branching of the pulmonary blood vessels and coordinates their development with that of the airways. The specific aims are: (1) To define the patterns and cellular mechanisms of the branching events in pulmonary vascular development and their relationship to, and dependence on, the airways and other lung tissues in the developing mouse lung; (2) To map spatial patterns of gene expression on a genome-wide scale in the developing mouse lung, including analysis of their relative expression patterns and the relationship of these patterns to the morphological and cellular events defined in Aim 1. Genes analyzed will include all known signaling molecules, receptors, and genes induced by signaling pathways, and genes implicated in blood vessel development; (3) To establish a method for misexpressing and inactivating lung development genes in highly localized regions and at different positions in the embryonic mouse lung, and to use the method to evaluate the function of two genes potentially involved in the coordination of vascular and airway development.