Functional Genomics of Alveogenesis

描述(由申请人提供)：对肺发育的全面了解有助于制定旨在改善与未成熟和未能修复受损成人肺组织相关的疾病的策略。我们认为，高度复杂、相互关联但分子上离散的生物学过程控制着肺的发育。表达谱分析是一项新兴技术，它允许从给定的细胞或组织中生成高度详细的基因表达图。这些图谱可用于区分正常和异常情况，以及根据表达模式的相似性生成共享生化/分子途径的基因之间的假定功能关系。我们已经启动了对小鼠肺发育整个过程的表达谱研究，以努力全面了解相关的分子过程。特别是，我们最感兴趣的是控制终末肺发育和肺泡形成的机制，这一过程的调节一直难以捉摸。我们对这些数据的初步分析集中在对ECM生产的监管上。由于ECM既提供结构支持，又提供细胞因子和结构信号的来源，对其建立的全面了解将为肺发育的基本机制提供重要信息。我们的初步数据有力地表明，功能基因组学方法可以识别控制肺发育的调控网络。特别是，数据的一个子集涉及FGFR3/R4信号，这是牙槽形成过程中必不可少的，在基底膜(BM)组成的调节中。这些研究将建立终末肺发育的全面分子图谱，并验证FGFR信号在肺泡形成过程中控制基底膜成分的假设。为了实现这些目标，我们将1)通过全基因组表达谱确定控制肺泡形成的调控网络，2)研究FGFR相关的基底膜基因在终末肺发育中的调控，3)确定FGFR3/4依赖的肺泡发生的分子机制。

DESCRIPTION (provided by applicant): A comprehensive understanding of lung development could assist the development of strategies aimed at ameliorating disease associated with incomplete maturation and failure to repair damaged adult lung tissue. We believe that highly complex, inter-related yet molecularly discrete biological processes control pulmonary development. Expression profiling is an emerging technology that allows the generation of a highly detailed map of the gene expression from a given cell or tissue. These maps can be used to discriminate normal from abnormal conditions, as well as generate putative functional relationships between genes sharing biochemical/molecular pathways based upon similarities in expression patterns. We have initiated expression-profiling studies of the entire process of lung development in the mouse in an effort to comprehensively understand the relevant molecular processes. In particular, we are most interested in the mechanisms that govern terminal lung development and alveogenesis, a process whose regulation has been elusive. Our initial analysis of these data has focused upon regulation of ECM production. As the ECM provides both a structural support and a source of cytokine and structural signaling, a complete understanding of its establishment should provide important information regarding essential mechanisms of lung development. Our preliminary data strongly suggests a functional genomics approach can identify regulatory networks controlling lung development. In particular, a sub-set of the data implicates FGFR3/R4 signaling, which is essential to the process of alveogenesis, in the regulation of basement membrane (BM) composition. The studies proposed will establish a comprehensive molecular map of terminal lung development and test the hypothesis that FGFR signaling controls basement membrane composition during alveogenesis. In order to achieve these goals, we will 1) identify regulatory networks controlling lung alveogenesis by genome-wide expression profiling, 2) investigate FGFR-related basement membrane gene regulation in terminal lung development, 3) define the molecular mechanisms involved in FGFR3/4-dependent alveogenesis.