The Gene Expression Program of Mouse Lung Development

描述(由申请人提供)： 肺由两个相互关联的分支管状网络组成，即呼吸道和肺血管，它们汇聚在肺泡内，血液在肺泡内复氧。这些网络结构或其关联的结构缺陷可导致或促成严重的肺部疾病，但对这些复杂的分支结构如何在发育过程中出现或其结构如何协调知之甚少。肺开始发育为一对被原始血管网络包围的空气管(支气管)。随后，数以百万计的呼吸道分支与类似数量的动脉和静脉一起萌发。少数在最初的呼吸道分支事件中起作用的基因和信号通路已被确定，但在人类、小鼠或其他动物中，控制肺血管发育并协调其与呼吸道发育的遗传程序尚未阐明。这笔赠款的长期目标是阐明控制肺血管形成和分支的遗传程序，并协调它们与呼吸道的发育。其具体目的是：(1)确定肺血管发育中分支事件的模式和细胞机制，以及它们与发育中的小鼠肺的呼吸道和其他肺组织的关系和依赖；(2)绘制发育中小鼠肺中基因表达的空间模式图，包括分析它们的相对表达模式，以及这些模式与目标1中定义的形态和细胞事件的关系。所分析的基因将包括所有已知的信号分子、受体和信号通路诱导的基因，以及与血管发育有关的基因；(3)建立小鼠胚胎肺高度定位区和不同位置肺发育基因错误表达和失活的方法，并利用该方法评价两个可能参与血管和呼吸道发育协调的基因的功能。

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.