Systems approach to identify phosphoregulators of mouse lung development

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DESCRIPTION (provided by applicant): A major goal in understanding tissue and organ formation is to link key developmental signals to the fundamental molecular pathways responsible for guiding and controlling such development. The genomic era has created a tremendous body of knowledge and provided a global overview of the molecular regulators of the cell. However, there is a considerable gap in understanding the function of these regulators and even wider gap in understanding the links between these regulators and the mechanisms by which they generate complex three-dimensional tissues. The current state-of-the-art requires a comprehensive approach or systems approach in which the interaction between pathways and the complexity created by the convergence of different pathways must be addressed to further our understanding of the development of key organs relevant to human health and disease. The proposed research project aims at filling this gap by generating a comprehensive understanding of the functional relationship between kinase/phosphatase regulated molecular pathways and their roles in organizing the formation of the embryonic mouse lung. This proposal utilizes a variety of established as well as new and innovative cell biological and developmental techniques to pursue the following aims. Aim 1 will define the kinases and phosphatases involved in embryonic lung morphogenesis using a combination of a functional genomics (loss of function) screen with morphological analysis in lung explant cultures. Aim 2 will define the molecular pathways involved in lung morphogenesis, correlating known molecular pathway regulators among the kinome/phosphatome with hits from our loss of function screen. Within 2 years our approach will lead to a fundamental understanding of how lung morphogenesis is controlled by phosphoregulatory proteins and the cross-talk between key developmental signals. A long term goal is to provide potential targets for the treatment of human diseases including lung cancer, emphysema, asthma, and the immature lungs of premature infants. PROJECT NARRATIVE. The overall goal is to use a comprehensive systematic approach to provide a fundamental understanding of the essential molecular regulators of embryonic lung development. These findings have the potential to provide possible new targets for the treatment of the immature lungs of premature infants and of human diseases including lung cancer, emphysema, and asthma.