How does pituitary androgen signalling support lifelong health and wellbeing? An integrated transgenic and systems biology approach

脑下垂体对身体有着如此大的影响力，它通常被称为“主腺”。它位于大脑的底部，通过分泌影响许多器官和组织功能的循环激素来响应局部和循环因素，以支持身体的健康和福祉。脑垂体产生的每种激素都是由一种独特的细胞类型产生的，这些细胞连接在一起，在腺体内形成自己的网络。目前，我们还不完全了解垂体细胞如何响应来自身体其他部位的信号来控制这些激素的产生。睾酮由睾丸产生，是男性身体健康发育和功能所必需的，但女性也会少量产生睾酮。睾丸激素受体（称为雄激素受体）存在于脑垂体的所有细胞类型中。以前认为睾丸激素是产生一种叫做促黄体激素的脑垂体激素所必需的（它本身控制睾丸在负反馈回路中产生睾酮），然而，在最近一项使用转基因小鼠的突破性研究中，我们已经表明，通过敲除雄激素受体来阻断垂体中的睾酮信号，改变了两种垂体激素的产生：催乳素和生长激素，但不是促黄体生成激素。总之，这些令人兴奋的发现表明，我们对雄激素在垂体中的作用的理解还远远没有完成，迫切需要重新评估这个系统。因此，在这个项目中，我们的目标是明确地建立雄激素信号在垂体中的基本作用，以及它如何支持终身健康和福祉。我们将首先使用我们以前BBSRC资助的项目中建立的软件来制作脑垂体激素生产的计算机模拟。这将把所有已发表的关于垂体功能的信息合并到一个位置，并将在整个项目中用于支持实验设计，结果反馈到模型中，以完善我们的理解。在我们的实验室实验中，我们将使用小鼠作为模型，因为它们的垂体含有雄激素受体，并产生与人类相同的激素。我们还可以通过删除基因来操纵老鼠的遗传学（称为敲除或通过使用小鼠基因来控制标记特定细胞类型的荧光报告基因的产生。首先，我们将在催乳素产生细胞（催乳素细胞）内敲除睾酮信号，以确定循环催乳素浓度是否受催乳素分泌细胞或其他垂体中睾酮的控制细胞类型。我们将确定睾酮如何正常抑制催乳素的产生，以及垂体内催乳素细胞网络的组织是否由睾酮形成。我们将定义睾酮在控制垂体生长激素产生细胞（生长激素细胞）中的作用。我们将确定睾酮是否控制生长激素分泌的频率，以及垂体内促生长激素细胞的组织是否由睾酮形成。我们还将确定睾酮在垂体的促黄体生成激素产生细胞（促性腺激素细胞）中的作用。我们将剖析睾酮、催乳素和促黄体生成素之间的相互作用，确定这些激素如何在垂体中共同发挥作用。最后，我们将确定雄激素受体在女性垂体中的定位，以及阻断睾酮信号是否会影响女性的发情周期或怀孕。该项目的完成将导致我们对垂体睾酮信号作用的理解的全面重新定义;显着提高我们对终身健康和福祉维护的理解。

The pituitary gland holds such influence over the body it is commonly dubbed the 'master gland'. Located at the base of the brain, it responds to local and circulating factors by secreting circulating hormones that influence the function of many organs and tissues to support the body's health and wellbeing. Each hormone made by the pituitary is produced by a unique cell-type, which link together to form their own networks inside the gland. Currently we don't completely understand how the pituitary's cells respond to signals from the rest of the body to control the production of these hormones. Testosterone is produced by the testes and is required for healthy development and function of men's bodies, but is also made in small amounts by women too. Receptors for testosterone (called androgen receptors) are found inside all of the cell types in the pituitary gland. It was previously thought that testosterone was required for the production of a pituitary hormone called luteinising hormone (that itself controls the production of testosterone by the testes in a negative feedback loop), however in a recent ground-breaking study using transgenic mice we have shown that blocking of the testosterone signal in the pituitary by knocking out androgen receptors, changes production of two of the pituitary hormones: prolactin and growth hormone, but not luteinising hormone. Taken together, these exciting findings demonstrate that our understanding of the role of androgens in the pituitary is far from complete and that an urgent re-evaluation of this system is required. Therefore in this project, we aim to unequivocally establish the fundamental role(s) for androgen signalling in the pituitary, and how this supports lifelong health and wellbeing. We will first produce a computer simulation of pituitary hormone production using software established in our previous BBSRC-funded projects. This will coalesce all of the published information on pituitary function into a single location and will be used throughout the project to support experimental design, with results fed back into the model to refine our understanding. In our laboratory experiments, we will use mice as a model as their pituitaries contain androgen receptor and produce the same hormones as humans. We can also manipulate the genetics of the mouse by the deletion of genes (known as knockouts or by using mouse genes to control the production of fluorescent reporter genes that label specific cell types.Firstly, we will knockout testosterone signalling just within the prolactin-producing cells (lactotrophs) of the male pituitary to determine whether circulating prolactin concentration is controlled by testosterone in the lactotroph or in another pituitary cell-type. We will determine how testosterone normally suppresses prolactin production, and whether the organisation of the network of lactotroph cells within the pituitary is shaped by testosterone. We will define the role of testosterone in controlling the growth hormone-producing cells of the pituitary (the somatotrophs). We will determine whether testosterone controls the frequency of growth hormone secretion, and whether the organisation of somatotroph cells within the pituitary is shaped by testosterone.We will also define the role of testosterone in the luteinising hormone producing cells of the pituitary (the gonadotrophs). We will dissect the interplay between testosterone, prolactin and luteinising hormone, establishing how these hormones work together in the pituitary.Finally we will determine the localisation of androgen receptor in the female pituitary, and whether blocking the testosterone signal in females impact the estrous cycle or pregnancy. Completion of this project will result in a comprehensive redefinition of our understanding of the roles for pituitary testosterone signalling; significantly improving our understanding of the maintenance of lifelong health and wellbeing.