The role of theca cells in ovarian follicle atresia in cattle

在过去的50年里，全球奶牛的繁殖力大幅下降，以至于北美平均70%的奶牛群处于亚生育力状态。这是一项重大的收入损失，养育额外牛只的环境成本正变得不可接受。我的NSERC研究项目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。*女性不孕可能是由卵巢、子宫或脑下垂体的问题引起的。我的研究重点是卵巢。在卵巢中，卵子(卵母细胞)被包含在一个叫做卵泡的充满液体的结构中。在牛和人类等物种中，几个卵泡在发情周期的开始时开始同步生长，但只有一个长得足够大，在排卵时释放一个卵子；其余的卵泡退化。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。*卵泡包含三种主要细胞类型，卵母细胞、颗粒细胞和膜细胞。在过去的10年里，人们对卵母细胞和颗粒细胞之间的激素相互作用进行了大量的研究。这是合乎逻辑的，因为当卵泡开始退化时，颗粒细胞受到的影响最大；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，证明另一种细胞类型--膜细胞--可能在使颗粒细胞对死亡信号敏感方面发挥作用。我们鉴定了成纤维细胞生长因子激素家族中的一个非典型成员，FGF18，当应用于培养中的颗粒细胞时，它会导致细胞死亡，并且与健康卵泡相比，退行性卵泡膜细胞分泌的FGF18浓度更高。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FGF18的因素，(B)确定FGF18对颗粒细胞的作用机制，以及(C)寻找可能决定卵巢卵泡命运的由卵泡膜细胞分泌的其他因素。*识别导致颗粒细胞死亡的膜细胞分泌的因素将为防止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毛囊生长曲线的物种，包括绵羊、马和濒危物种。

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.**