STEROID HORMONE SYNTHESIS/INACTIVATION AND ACTION IN TERMINAL LUNG DEVELOPMENT

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The goal of this study is to characterize the role of androgens in the development of 3D lung structure. Androgens are known as male sex steroids but they exist in the blood of both sexes, although at higher levels for males. We showed in a recent experiment that when the effect of androgens is blocked by administration of a pure antiandrogen (flutamide) to neonatal mice, the last step of lung development (alveolarization) is altered and an obvious defect in lung structure is observed. Surprisingly, our data indicate that flutamide had the same effect in both sexes, showing that androgens are essential for normal lung development of males and females. We know that several genes expressed in the developing lung encode for enzymes showing the capability to synthesize active androgens from an inactive molecule, while other genes produce enzymes able to inactivate androgens. Our hypothesis in this grant is that site-specific expression of the genes involved in androgen synthesis and inactivation results in a multitude of microenvironments with site-specific levels of androgens, which control the development of the 3D structure of the lung. This concept indicates that growth of the lung along each axis (x,y,z) is a tightly orchestrated process. During the next 5 years, I propose to study the involvement of the androgen activating and inactivating genes in lung development: 1) by studying their levels of expression over time during lung development; 2) by characterizing their exact site of expression in the developing lung at different developmental times, and; 3) by examining the lung structure after administration of gene-specific inhibitors (siRNA). This study will be performed in 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.