The present application focuses its primary attention to discerning the principles of lung morphogenesis and repair in vivo and is based on the ability to precisely target, mutate or add genes to respiratory epithelial cells and mesenchymal cells of the developing mouse embryo. Major breakthroughs have been made by the SCOR investigators in developing conditional systems for gene regulation in vivo, now enabling gene targeting, via doxycycline controlled cre-recombinase in the developing and mature lung. These new technologies will be applied to important pathways mediating 1) lung formation (TTF-1, HNF-3beta and FGF-signaling pathways; 2) lung function, remodeling and inflammation (SP-C and SP-D). Clinical translation of information gained from these molecular models will extend our understanding of the cellular signals and molecular events regulating development and the pathogenesis of acquired lung disease in neonates and adults. Each project will require the generation and analysis of transgenic mice in which the animal is modified by adding correct or mutated genes which are expected to alter lung development or lung function in unique ways. The analysis data from each of the planned projects requires shared scientific expertise, approaches and reagents, and use similar biochemical, immunochemical, histologic, metabolic and physiological endpoints. The comprehensive analysis of each of the various gene knockouts and gene addition experiments are best accomplished in context of highly organized Core settings where developing technology, reagents and ideas can be rapidly shared among the various investigators. Cores for Molecular Morphology, Transgenic Animals, and Clinical Studies will greatly facilitate the scientific progress of the individual projects. Project 1. Respiratory Epithelial Cell Differentiation (TTF-1, HNF-3beta), J. A. Whitsett, P.I. Project 6. Fibroblast Growth Factors in Lung Morphogenesis, J. Shannon, P.I. Project 2. Role of SP-D in Pulmonary Remodeling, T. Korfhagen, P.I. Project 7. SP-C Mutations and Neonatal Lung Disease, T. E. Weaver, P.I. Core 9004. Transgenic Core, J.A. Whitsett, P.I. Core 9002. Morphology Core, S. Wert, J. Shannon, P.I. Core 9005. Clinical Core, S. Wert, P.I.
