Steroid hormone synthesis/inactivation and action in terminal lung development

目的是研究雄激素在肺三维结构发育中的作用。虽然雄激素对表面活性剂合成激增的负面影响是有据可查的，但雄激素被均匀地提出作为肺发育早期分支形态发生的正调节剂，以及作为两性肺发育晚期的重要调节剂。因此，雄激素不是男性独有的。它们在两种性别的胎儿肺中被发现，并且我们已经证明，在胎儿和出生后的肺发育过程中，催化从血液前体形成雄激素和这些雄激素失活的基因在发育中的肺中细胞特异性表达。最近，我们发现在出生后肺发育期间，雄性和雌性肺的几个上皮细胞中存在核转位雄激素受体。这证明它们是在终末肺发育期间在两性中受雄激素调节的基因。雄激素通过刺激细胞增殖和程序性细胞死亡（PCD）来刺激分支形态发生，并且我们发现，在胎儿肺发育后期，雄激素均匀地调节参与细胞增殖和PCD的基因。因此，类固醇基因催化雄激素合成和失活，并在发育中的肺细胞特异性表达，可能参与肺的三维结构的发展。这一假设将在今后5年内进行研究。我们将研究雄激素代谢，并确定在出生后的小鼠肺雄激素合成的基因表达的网站为两种性别;研究的影响，去除性腺和抑制的三个基因的表达参与雄激素代谢在终端肺发育的两种性别。雄激素调节3D肺发育的潜力使这个基础研究项目对所有从事器官发生和组织工程的研究人员非常有用。

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.