Functional Genomics of Alveogenesis

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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.