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

垂体雄激素信号如何支持终生健康和福祉？

• 批准号: BB/N007026/1
• 负责人: Lee Smith
• 金额: $ 53.78万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN007026%2F1
• 关键词: How; does; pituitary; androgen; signalling

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.

脑下垂体对身体有这样的影响，它通常被称为“主腺”。它位于大脑底部，通过分泌循环激素来响应局部和循环因素，这些激素影响许多器官和组织的功能，以支持身体的健康和幸福。脑下垂体产生的每一种激素都是由一种独特的细胞类型产生的，这些细胞类型连接在一起，在腺体内形成自己的网络。目前我们还不完全了解脑垂体细胞是如何对来自身体其他部位的信号做出反应来控制这些激素的产生的。睾丸素是由睾丸产生的，是男性身体健康发育和功能所必需的，但女性也会产生少量的睾丸素。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。以前人们认为，一种叫做黄体生成素的垂体激素的产生需要睾丸激素（黄体生成素本身控制睾丸激素的产生，形成负反馈循环），然而，在最近一项利用转基因小鼠的突破性研究中，我们发现，通过敲掉雄激素受体来阻断垂体中的睾丸激素信号，会改变垂体中两种激素的产生：催乳素和生长激素，但不是促黄体生成素。综上所述，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不够完整，迫切需要对这一系统进行重新评估。因此，在本项目中，我们的目标是明确确定垂体中雄激素信号的基本作用，以及它如何支持终身健康和福祉。我们将首先使用在我们之前的bbsrc资助项目中建立的软件制作垂体激素产生的计算机模拟。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，并将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（称为敲除）或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来操纵小鼠的遗传学。首先，我们将敲除男性垂体泌乳素产生细胞（乳滋养细胞）内的睾酮信号，以确定循环泌乳素浓度是否由乳滋养细胞或另一种垂体细胞类型中的睾酮控制。我们将确定睾酮通常如何抑制催乳素的产生，以及垂体内乳营养细胞网络的组织是否由睾酮塑造。我们将定义睾酮在控制垂体生长激素生成细胞（生长激素）中的作用。我们将确定睾丸激素是否控制生长激素分泌的频率，以及垂体内生长发育不良细胞的组织是否受睾丸激素的影响。我们还将定义睾酮在垂体（促性腺）的促黄体激素产生细胞中的作用。我们将剖析睾酮、催乳素和黄体生成素之间的相互作用，确定这些激素如何在脑垂体中协同工作。最后，我们将确定雌性垂体中雄激素受体的定位，以及阻断雌性激素信号是否会影响发情周期或妊娠。该项目的完成将导致我们对垂体睾丸激素信号作用的理解的全面重新定义；大大提高了我们对维持终身健康和幸福的理解。

项目成果

Characterisation of a mural cell network in the murine pituitary gland.

小鼠垂体壁细胞网络的表征。

• DOI: 10.1111/jne.12903
• 发表时间: 2020
• 期刊: Journal of neuroendocrinology
• 影响因子: 3.2
• 作者: O'Hara L

Modelling steroidogenesis: a framework model to support hypothesis generation and testing across endocrine studies.

• DOI: 10.1186/s13104-018-3365-y
• 发表时间: 2018-04-24
• 期刊: BMC research notes
• 影响因子: 1.8
• 作者: O'Hara L;O'Shaughnessy PJ;Freeman TC;Smith LB
• 通讯作者: Smith LB

Imaging and Manipulating Pituitary Function in the Awake Mouse.

清醒小鼠的垂体功能成像和操作。

• DOI: 10.1210/en.2019-00297
• 发表时间: 2019
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Hoa O

Modelling the Structure and Dynamics of Biological Pathways.

生物途径的结构和动力学建模。

• DOI: 10.1371/journal.pbio.1002530
• 发表时间: 2016-08
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: O'Hara L;Livigni A;Theo T;Boyer B;Angus T;Wright D;Chen SH;Raza S;Barnett MW;Digard P;Smith LB;Freeman TC
• 通讯作者: Freeman TC

Hyperprolactinemia in a male pituitary androgen receptor knockout mouse is associated with female-like lactotroph development.

雄性垂体雄激素受体敲除小鼠的高催乳素血症与雌性催乳素发育相关。

• DOI: 10.1111/andr.13040
• 发表时间: 2021
• 期刊: Andrology
• 影响因子: 4.5
• 作者: O'Hara L