The role of theca cells in ovarian follicle atresia in cattle

卵泡膜细胞在牛卵巢卵泡闭锁中的作用

• 批准号: RGPIN-2015-05921
• 负责人: Price, Christopher
• 金额: $ 4.15万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=613825
• 关键词: role; theca; cells; ovarian; follicle

Over the last 50 years, there has been a major decline in fertility in dairy cattle worldwide, such that 70% of the average North American dairy herd is subfertile. This represents a major loss of income and the environmental cost of maintaining extra cattle for breeding is becoming inacceptable. The long-term goal of my NSERC research program is to understand the mechanisms of infertility in cattle, in order to propose solutions for the Canadian dairy industry. Infertility in females can be caused by problems at the level of the ovary, the uterus or the pituitary gland. My research focuses on the ovary. In the ovary, the egg (oocyte) is contained within a fluid-filled structure called the follicle. In species such as cattle and humans, several follicles start to grow synchronously at the beginning of an estrous cycle, but only one grows large enough to release an egg at ovulation; the remainder regress. The reasons why follicles regress are not clear, but likely involves a complex series of hormonal interactions within the follicle. The follicle contains three major cell types, the oocyte, granulosa cells and theca cells. Over the last 10 years, there has been a lot of research into the hormonal interactions between the oocyte and granulosa cells. This is logical, as when a follicle starts to regress, it is the granulosa cells that are most affected; they cease secreting important hormones and they show signs of cell death. However, my lab has recently provided novel evidence that the other cell type, the theca cell, may play a role in sensitizing granulosa cells to death signals. We identified an atypical member of the Fibroblast Growth Factor family of hormones, FGF18, that causes cell death when applied to granulosa cells in culture, and which is secreted in higher concentrations from theca cells of regressing compared to healthy follicles. In this next phase of my programme, we will (a) determine the factors that increase FGF18 secretion from theca cells, (b) determine the mechanism of action of FGF18 on granulosa cells, and (c) search for other factors secreted by theca cells that may determine the fate of the ovarian follicle. Identifying factors secreted by theca cells that cause granulosa cell death will provide treatment options to prevent follicle regression. This would be applicable to cattle, and potentially to other species that undergo the same profile of follicle growth, including sheep, horses and endangered species.

在过去的50年里，全世界奶牛的生育力大幅下降，北美平均70%的奶牛群生育力低下。这是一项重大的收入损失，而饲养额外的牛只进行繁殖的环境代价也变得不可接受。我的NSERC研究计划的长期目标是了解牛不育的机制，以便为加拿大乳制品行业提出解决方案。 女性不孕症可能是由卵巢、子宫或脑垂体水平的问题引起的。我的研究重点是卵巢。在卵巢中，卵子（卵母细胞）包含在一个充满液体的结构中，称为卵泡。在牛和人类等物种中，在发情周期开始时，几个卵泡开始同步生长，但只有一个卵泡生长到足以在排卵时释放卵子;其余卵泡退化。卵泡退化的原因尚不清楚，但可能涉及卵泡内一系列复杂的激素相互作用。 卵泡包含三种主要的细胞类型：卵母细胞、颗粒细胞和卵泡膜细胞。在过去的10年里，有很多关于卵母细胞和颗粒细胞之间激素相互作用的研究。这是合乎逻辑的，因为当卵泡开始退化时，受影响最大的是颗粒细胞;它们停止分泌重要的激素，并显示出细胞死亡的迹象。然而，我的实验室最近提供了新的证据，表明另一种细胞类型，卵泡膜细胞，可能在颗粒细胞对死亡信号的敏感性中发挥作用。我们鉴定了成纤维细胞生长因子家族的激素FGF 18的非典型成员，其在应用于培养物中的颗粒细胞时引起细胞死亡，并且与健康卵泡相比，其以更高浓度从退化卵泡膜细胞分泌。在我的计划的下一阶段，我们将（a）确定增加卵泡膜细胞分泌FGF 18的因素，（B）确定FGF 18对颗粒细胞的作用机制，（c）寻找卵泡膜细胞分泌的其他可能决定卵泡命运的因素。 识别卵泡膜细胞分泌的导致颗粒细胞死亡的因子将为预防卵泡退化提供治疗选择。这将适用于牛，并可能适用于其他经历相同卵泡生长特征的物种，包括羊、马和濒危物种。