Steroid hormone synthesis/inactivation and action in terminal lung development

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The goal is to study the role of androgens in the development of the 3D structure of the lung. Although the negative effect of androgens on the surge of surfactant synthesis is well documented, androgens were evenly proposed as positive regulators of branching morphogenesis in early lung development, and as important regulators of late lung development in both sexes. Accordingly, androgens are not exclusive to males. They were found in the fetal lung of both sexes and we have demonstrated that genes catalyzing the formation of androgens from a blood precursor and the inactivation of these androgens are cell-specifically expressed in the developing lung during fetal as well as post-natal lung developments. Recently, we showed nuclear translocated androgen receptor in several epithelial cells of the female and male lungs during the post-natal period of lung development. This attests that they are genes which are under androgen regulation in both sexes during terminal lung development. Androgens were shown to stimulate branching morphogenesis by stimulating cell proliferation and programmed cell death (PCD) and we found that genes involved in cell proliferation and PCD are evenly modulated by androgens later in fetal lung development. Therefore, steroidogenic genes catalyzing androgen synthesis and inactivation and being cell-specifically expressed in the developing lung are likely to be involved in the development of the 3D structure of the lung. This hypothesis will be studied during the next 5 years. We will study androgen metabolism, and determine the site of expression of genes involved in androgen synthesis in post-natal mouse lungs for both sexes; study the effect of removing gonads and of the inhibition of expression of three genes involved in androgen metabolism in terminal lung development of both sexes. The potential of androgens to modulate 3D-lung development makes this fundamental research program very useful for all researchers working on organogenesis and tissue engineering.