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的负面影响已被充分证明，但雄激素在早期肺发育中是分支形态发生的积极调节因子，在两性中也是晚期肺发育的重要调节因子。因此，雄激素并不是雄性所独有的。它们在两性胎儿肺中都被发现，我们已经证明，从血液前体中催化雄激素形成的基因和这些雄激素的失活是在胎儿和出生后肺部发育期间在肺发育中细胞特异性表达的。最近，我们发现在出生后肺发育期间，雌性和雄性肺的几个上皮细胞中存在核易位雄激素受体。这证明它们是在晚期肺发育过程中受雄性激素调控的基因。雄激素被证明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，我们发现在胎儿肺发育后期，雄激素均匀地调节了参与细胞增殖和PCD的基因。因此，促雄激素合成和失活并在发育中的肺细胞特异性表达的类固醇基因很可能参与了肺三维结构的形成。这一假设将在未来5年进行研究。我们将研究雄激素代谢，并确定雌雄小鼠出生后肺中雄激素合成相关基因的表达位点；研究切除性腺及抑制雄激素代谢相关基因表达对两性肺末梢发育的影响。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.