Steroid hormone synthesis/inactivation and action in terminal lung development

类固醇激素合成/失活及其在肺终末发育中的作用

• 批准号: 171140-2010
• 负责人: Tremblay, Yves
• 金额: $ 2.19万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2012
• 资助国家: 加拿大
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=506575
• 关键词: Steroid; hormone; synthesis; inactivation; action

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.

目的是研究雄激素在肺三维结构发育中的作用。虽然雄激素对肺表面活性物质合成激增的负面影响已有文献记载，但在早期肺发育中，雄激素被认为是分支形态发生的正调节因子，而在肺发育后期，雄激素被认为是重要的调节因子。因此，雄激素并不是男性独有的。我们已经证明，催化血液前体形成雄激素和使这些雄激素失活的基因在胎儿和出生后肺发育过程中是细胞特异性表达的。最近，我们发现在出生后肺发育期间，雄激素受体在雌性和雄性肺部的几个上皮细胞中发生了核移位。这证明它们是在终末肺部发育过程中处于雄激素调节下的基因。雄激素通过刺激细胞增殖和程序性细胞死亡(PCD)来刺激分枝形态发生，我们发现参与细胞增殖和PCD的基因在胎儿肺发育后期受到雄激素的均匀调控。因此，催化雄激素合成和失活的类固醇激素生成基因在发育中的肺中特异表达，可能参与肺三维结构的形成。这一假设将在未来5年内进行研究。我们将研究雄激素代谢，确定雄激素合成相关基因在出生后不同性别小鼠肺中的表达部位；研究去掉性腺和抑制三个雄激素代谢相关基因在终末肺发育中的作用。雄激素调节3D-肺发育的潜力使这一基础研究计划对所有从事器官发生和组织工程工作的研究人员非常有用。