Functional Genomics of Alveogenesis

描述（由申请人提供）：对肺发育的全面了解可以帮助制定旨在改善与不完全成熟和无法修复受损成人肺组织相关的疾病的策略。 我们认为，高度复杂的，相互关联的，但分子离散的生物过程控制肺的发展。 表达谱分析是一种新兴的技术，其允许从给定的细胞或组织产生高度详细的基因表达图谱。 这些图谱可用于区分正常与异常条件，以及基于表达模式的相似性产生共享生物化学/分子途径的基因之间的推定功能关系。 我们已经启动了小鼠肺发育整个过程的表达谱研究，以全面了解相关的分子过程。 特别是，我们最感兴趣的机制，管理终端肺的发展和肺泡，一个过程中的监管一直难以捉摸。 我们对这些数据的初步分析集中在ECM生产的调节上。 由于ECM提供了结构支持以及细胞因子和结构信号的来源，因此对其建立的完整理解应提供有关肺发育基本机制的重要信息。 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，数据的子集暗示FGFR 3/R4信号传导，这是至关重要的过程中的肺泡，在调节基底膜（BM）的组成。 这项研究将建立一个全面的终末肺发育的分子图谱，并测试在肺泡形成过程中FGFR信号控制基底膜组成的假设。 为了实现这些目标，我们将1）通过全基因组表达谱鉴定控制肺泡形成的调控网络，2）研究终末肺发育中FGFR相关的基底膜基因调控，3）确定参与FGFR 3/4依赖性肺泡形成的分子机制。

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.