New models for the onset of virilisation in the developing male

男性化障碍是人类最常见的发育缺陷之一，但超过一半的情况不能用我们目前的知识来解释。对这些过程的研究受到阻碍，因为大多数哺乳动物的男性化发生在子宫中，也就是早期胎儿。我们最近对有袋类动物进行的研究表明，这个过程是由5-α-雄烷二醇介导的，这是一种以前未确定的生理功能的激素。我们将使用沙袋鼠进行实验，以测试解释为什么不同的男性组织--如生殖管、前列腺和阴茎--在非常不同的时间开始分化的假设。我们将研究雄激素的形成途径和激素在靶器官中的激活和失活，以及激素结合蛋白的作用。我们还将研究在阴茎早期发育过程中可能调节阴茎生长的生长因子的作用。这些实验的结果将在随后的几年中指导资金，以测试我们收集的200多个样本中相应的基因突变，这些样本来自原因尚不清楚的男性化缺陷(假两性畸形)患者。我们期望，这些研究的发现不仅将为睾丸激素使发育中的男性男性化的途径提供洞察力，还将解释人类中病因不明的男性假两性畸形的情况。

Impairment of virilisation is one of the most common developmental defects in humans, yet over half the cases cannot be explained by our current knowledge. Studies of these processes are hindered because in most mammals virilisation occurs in utero, in the early fetus. Our recent studies using marsupials, where virilisation occurs after birth show that this process is mediated by 5-alpha-androstanediol, a hormone with previously undetermined physiological function. We will conduct experiments using tammar wallabies, to test hypotheses that explain why different male tissues - such as the reproductive ducts, prostate and penis - start to differentiate at widely different times. We will investigate pathways of androgen formation and the activation and inactivation of hormones in the target organs, and the role of hormone binding proteins. We will also investigate the role of growth factors that may mediate growth of the penis during early development. The results of these experiments will direct funding in subsequent years to test for corresponding gene mutations in our collection of over 200 specimens from patients with defects of virilization (pseudohermaphroditism) whose causes are still unknown. It is our expectation that the findings in these studies will provide insight not only into the pathways by which testicular hormones masculinize the developing male, but will also explain instances of male pseudohermaphroditism of unknown aetiology in humans.