This application is based on the preliminary observation that the hematopoietic cytokine granulocyte macrophage colony stimulating factor (GM-CSF), plays a critical role in the regulation of alveolar Type Il cell growth and differentiation. GM-CSF (-/-) mice develop severe pulmonary alveolar proteinosis associated with accumulation of surfactant proteins and phospholipids in the airspace. This defect is completely corrected in bitransgenic mice expressing GM-CSF in the alveolar epithelium. Animals overexpressing GM-GSF also demonstrate marked alveolar Type Il cell hyperplasia. The present proposal utilizes in vivo and in vitro models to discern the role of GM-CSF and GM-CSF receptors in regulation of alveolar Type II cell growth and differentiation. The work is based on the hypothesis that autocrine and paracrine signalling between alveolar Type II epithelial cells and the alveolar macrophages, mediated by GM-CSF and the GM-CSF receptor, regulates the state of growth and differentiation of alveolar Type Il cells. The site of synthesis of GM-CSF will be determined in the developing and mature mouse lung. Bitransgenic GM-CSF (-/-) x SP-C- murine GM-GSF mice will be utilized to determine the stochastic, temporal and spatial requirements for the expression of GM-CSF which regulates Type II cell growth and differentiation. Production of GM-CSF in the lungs of transgenic mice will be controlled in a temporal fashion by utilizing a chimeric promoter enhancer construct, based on an SP-G promoter-tTA, tetracycline controllable element to modulate GM-CSF production in vivo. The time course for development of Type II cell hyperplasia will thus be assessed. Sites of expression and function of cytokine receptors involved in regulation of alveolar Type II cell growth and development will be discerned and the second messenger systems modulating GM-CSF effects determined. These studies are intended to derive further insight into the mechanisms mediating alveolar Type Il cell growth and differentiation, determining the role of autocrine and paracrine interactions, dependent upon GM-CSF, that modulate this growth.
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