The overall Objective of this project is to determine the molecular and cellular mechanisms that regulate fetal lung growth and maturation. Previous studies have shown that myc family proto-oncogenes play a key role in the regulation of cellular growth and differentiation. Preliminary data of ourselves and other indicate that the expression of c-myc in the developing lung is down-regulated near the time of onset of surfactant synthesis. We will take advantage of sex differences in the timing of lung maturation to determine the role of myc family gene expression in controlling fetal lung development. To accomplish our objectives four Specific Aims will be addressed.
Specific Aim #1 addresses the ontogeny of myc oncogenes in the fetal lung. Experiments will determine the time course of expression of c-myc, N-myc and L-myc in fetal rat, mouse, and rabbit lung in relation to the development of surfactant synthesis. In situ hybridization will determine the cell types expressing myc.
Specific Aim #2 addresses the mechanisms controlling the expression of myc in the fetal lung. Hormones (cortisol, estrogen, androgen, and thyroid), and growth factors (EGF,TGFBeta, and platelet-derived growth factor (PDGF), and interferon) will be used in organ culture and in cultured lung fibroblasts and type II cells to determine how myc expression is regulated and how changes of myc expression are correlated with the onset of maturation of the lung fibroblast and type II cell.
In Specific Aim #3, retroviral vectors harboring myc family proto- oncogenes will be used to determine the effects of constitutive myc expression on the maturation of lung fibroblasts and type II cells in culture.
In Specific Aim #4, myc expression vectors will be introduced into transgenic mice to determine the effects of constitutive myc gene expression on the development of the lung in vivo. The results of these experiments will lead to a better understanding of the mechanisms underlying fetal lung development. Such an understanding is crucial to developing strategies to prevent and treat Hyaline Membrane Disease of the newborn.
