Ovarian androgen synthesis: unravelling the roles of INSL3 and BMP signalling

卵巢雄激素合成：揭示 INSL3 和 BMP 信号传导的作用

• 批准号: BB/G017174/1
• 负责人: Philip Knight
• 金额: $ 55.19万
• 依托单位: University of Reading
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FG017174%2F1
• 关键词: Ovarian; androgen; synthesis; unravelling; roles

Fertility of female animals and humans requires the correctly-timed release of one or more healthy eggs (oocytes) from the paired ovaries. Eggs develop within structures called ovarian follicles which also produce a number of key hormones, without which reproduction is simply not possible. This research will investigate how the production of these hormones is regulated. In particular, two related hormones called androgen and oestrogen must be produced by specialized follicle cells in the right amounts - and at the right time - of the female cycle. Androgen is produced by cells called theca cells (TC) while oestrogen is produced by cells called granulosa cells (GC). GC can only synthesize oestrogen when they are supplied with androgen by neighboring TC. GC cannot synthesize androgen themselves and androgen is the essential precursor for oestrogen synthesis. Follicles grow from microscopic structures into large multi-layered, fluid filled structures ~ 2cm across (in human & cow). Pulses of luteinizing hormone (LH) from the pituitary stimulate TC to produce androgen while pituitary follicle-stimulating hormone (FSH) stimulates GC to proliferate and convert androgen into oestrogen. Mature follicles protrude from the ovary surface awaiting a hormone trigger from the pituitary (called the LH surge) that causes them to ovulate and release the egg for possible fertilization. This LH surge, in turn, depends on the secretion of increasing amounts of oestrogen by the growing follicle. In animals, this oestrogen rise also triggers vital behavioural changes ('heat') without which mating would not occur. Oestrogen also plays a key role in preparing the reproductive tract for pregnancy and both androgen and oestrogen affect many other tissues and organs. Thus, disordered follicle development leading to an imbalance in production of androgen by TC or of oestrogen by GC can not only cause infertility, but can affect many other aspects of physiology. For instance, a very common cause of infertility/subfertility in women called polycystic ovarian disease syndrome (PCOS) is associated with excess ovarian androgen production; this condition leads to disturbed menstrual cycles and excess growth of facial and body hair. Follicle development is a very complex process that is still poorly understood. It has been recognised recently that numerous signaling molecules are produced within the ovary itself that enable different cell-types to communicate with each other. This 'local' cell-cell communication must work in concert with signals from the pituitary (LH, FSH) to coordinate follicle growth and steroid production. In this project we will investigate the actions and interactions of two different 'local' signaling systems in regulating LH-induced androgen production by TC - the INSL3 system and the BMP system. Our decision to focus on these two systems is based on our recent discovery that (1) BMP can switch off production of both androgen and INSL3 by theca cells (2) a GC product called inhibin can, in turn, switch off BMP signaling and raise androgen production. In the project we will map the distribution of INSL3 (and its receptor) and various BMP system components (ligands, receptors, binding proteins) in follicles at different growth stages. We will also carry out detailed in vitro studies on TC (isolated from cow ovaries from the abattoir) to find out whether adding (or removing) different components of the INSL3, BMP or inhibin systems affects androgen production. In this way we will identify functional interactions between these different systems. Finally, we will find out if blood levels of INSL3 vary during the cow's oestrous cycle and if so, whether these changes are linked to patterns of follicle growth and levels of pituitary (LH, FSH) and ovarian (steroids, inhibin) hormone secretion. Collectively, these studies will significantly advance understanding of ovarian physiology and provide insights into a major cause of infertility.

雌性动物和人类的生育能力需要从配对的卵巢中正确定时释放一个或多个健康的卵子（卵母细胞）。卵子在称为卵泡的结构内发育，卵泡还产生许多关键激素，没有这些激素，繁殖根本不可能。这项研究将调查这些激素的产生是如何受到调节的。特别是，两种相关的激素，即雄激素和雌激素，必须由专门的卵泡细胞在女性周期的正确时间以正确的量产生。雄激素由称为卵泡膜细胞 (TC) 的细胞产生，而雌激素由称为颗粒细胞 (GC) 的细胞产生。 GC只有在邻近的TC提供雄激素的情况下才能合成雌激素。 GC本身不能合成雄激素，而雄激素是合成雌激素的重要前体。毛囊从微观结构生长成大型多层、充满液体的结构，直径约 2 厘米（人和牛）。来自垂体的黄体生成素 (LH) 脉冲刺激 TC 产生雄激素，而垂体促卵泡激素 (FSH) 刺激 GC 增殖并将雄激素转化为雌激素。成熟的卵泡从卵巢表面突出，等待垂体的激素触发（称为 LH 激增），导致它们排卵并释放卵子以进行可能的受精。反过来，LH 的激增取决于生长中的卵泡分泌的雌激素量的增加。在动物中，雌激素的增加还会引发重要的行为变化（“发情”），否则交配就不会发生。雌激素在生殖道怀孕准备中也发挥着关键作用，雄激素和雌激素都会影响许多其他组织和器官。因此，卵泡发育紊乱导致 TC 产生的雄激素或 GC 产生的雌激素不平衡，不仅会导致不孕，还会影响生理学的许多其他方面。例如，女性不孕/生育能力低下的一个非常常见的原因称为多囊卵巢疾病综合征（PCOS），与卵巢雄激素分泌过多有关。这种情况会导致月经周期紊乱以及面部和身体毛发过度生长。卵泡发育是一个非常复杂的过程，但人们对此仍知之甚少。最近人们认识到，卵巢本身会产生许多信号分子，使不同的细胞类型能够相互通讯。这种“局部”细胞间通讯必须与来自垂体（LH、FSH）的信号协同工作，以协调卵泡生长和类固醇产生。在这个项目中，我们将研究两种不同“局部”信号系统在调节 TC 诱导的 LH 雄激素产生方面的作用和相互作用 - INSL3 系统和 BMP 系统。我们决定关注这两个系统是基于我们最近的发现：(1) BMP 可以关闭卵泡膜细胞产生雄激素和 INSL3 (2) 一种称为抑制素的 GC 产物反过来可以关闭 BMP 信号传导并提高雄激素的产生。在该项目中，我们将绘制不同生长阶段卵泡中 INSL3（及其受体）和各种 BMP 系统成分（配体、受体、结合蛋白）的分布图。我们还将对TC（从屠宰场牛卵巢中分离出来）进行详细的体外研究，以了解添加（或去除）INSL3、BMP或抑制素系统的不同成分是否会影响雄激素的产生。通过这种方式，我们将识别这些不同系统之间的功能交互。最后，我们将了解 INSL3 的血液水平在奶牛的发情周期中是否变化，如果变化，这些变化是否与卵泡生长模式以及垂体（LH、FSH）和卵巢（类固醇、抑制素）激素分泌水平有关。总的来说，这些研究将显着增进对卵巢生理学的理解，并提供对不孕不育主要原因的见解。

项目成果

Comparison of bioactivities, binding properties and intrafollicular levels of bovine follistatins.

牛卵泡抑素的生物活性、结合特性和卵泡内水平的比较。

• DOI: 10.1530/rep-15-0086
• 发表时间: 2015
• 期刊: Reproduction (Cambridge, England)
• 作者: Glister C

The anti-epileptic drug valproic acid (VPA) inhibits steroidogenesis in bovine theca and granulosa cells in vitro.

• DOI: 10.1371/journal.pone.0049553
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Glister C;Satchell L;Michael AE;Bicknell AB;Knight PG
• 通讯作者: Knight PG

Reproduction in Domestic Ruminants

家养反刍动物的繁殖

• 发表时间: 2014
• 作者: Knight PG

Gremlin, noggin, chordin and follistatin differentially modulate BMP-induced suppression of androgen secretion by bovine ovarian theca cells

• DOI: 10.1530/jme-18-0198
• 发表时间: 2019-01-01
• 期刊: JOURNAL OF MOLECULAR ENDOCRINOLOGY
• 影响因子: 3.5
• 作者: Glister, Claire;Regan, Sheena L.;Knight, Phil G.
• 通讯作者: Knight, Phil G.