Novel mechanisms of theca cell growth in the ovarian follicle of cattle

牛卵巢卵泡膜细胞生长的新机制

• 批准号: RGPIN-2021-03014
• 负责人: Price, Christopher
• 金额: $ 4.01万
• 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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746069
• 关键词: Novel; mechanisms; theca; cell; growth

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 genetic diversity and huge economic and environmental costs. 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 is mostly caused by problems at the level of the ovary, and my research focuses on the follicle, a fluid-filled structure that contains the egg (oocyte). Several follicles start to grow synchronously at the beginning of an estrous cycle, but in species such as cattle and horses, 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, and there has been a lot of research into the hormonal interactions between these cell types. Theca cells reside in a fibrous layer that also contains blood capillaries and connective tissue. My lab has been investigating a factor ('FGF18') that is secreted by the theca cell layer and that causes granulosa cell death, and we recently discovered that this factor is secreted not by theca cells but by the cells of the blood capillaries (endothelial cells). These cells are controlled by hormones and also by physical forces, including being stretched within growing tissues. As the growing follicle expands by 10% per day, we hypothesize that theca cells are also subject to biophysical forces that shape their function. In this next phase of my program, we will (1) establish a 'stretch' model of bovine theca cells in culture, (2) determine the main pathways regulated by stretch in theca cells, and (3) discover novel signaling from theca cells in response to stretch. To achieve these goals, my team of graduate students will develop a method for 'stretching' theca cells in culture, and determine how theca cells detect and respond to biophysical force. We will then identify novel factors secreted by theca cells in response to stretch, and determine the effect that these factors have on granulosa cell health and growth of the follicle. This research may provide new approaches to improving fertility in cattle, and potentially to other species that undergo the same type of follicle growth, including sheep, horses and endangered species.

在过去的50年里，世界范围内奶牛的生育力大幅下降，北美平均70%的奶牛生育力不足。这意味着遗传多样性的重大损失以及巨大的经济和环境成本。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。女性不孕症主要是由卵巢层面的问题引起的，我的研究重点是卵泡，一个充满液体的结构，包含卵子（卵母细胞）。几个卵泡在发情周期开始时开始同步生长，但在像牛和马这样的物种中，只有一个卵泡长到足以在排卵期排卵；其余的回归。卵泡退化的原因尚不清楚，但可能与卵泡内一系列复杂的激素相互作用有关。卵泡包含三种主要的细胞类型，卵母细胞、颗粒细胞和卵泡细胞，人们对这些细胞类型之间的激素相互作用进行了大量研究。鞘膜细胞位于含有毛细血管和结缔组织的纤维层中。我的实验室一直在研究一种由膜细胞层分泌的因子（FGF18），它会导致颗粒细胞死亡，我们最近发现这种因子不是由膜细胞分泌的，而是由毛细血管细胞（内皮细胞）分泌的。这些细胞受到激素和物理力量的控制，包括在生长的组织中被拉伸。随着卵泡每天以10%的速度扩张，我们假设卵泡细胞也受到生物物理力量的影响，从而塑造了它们的功能。在我的计划的下一阶段，我们将(1)建立一个培养的牛卵膜细胞的“拉伸”模型，(2)确定卵膜细胞中拉伸调节的主要途径，(3)发现卵膜细胞响应拉伸的新信号。为了实现这些目标，我的研究生团队将开发一种“拉伸”培养中的卵泡膜细胞的方法，并确定卵泡膜细胞如何检测和响应生物物理力。然后，我们将确定由卵泡细胞在拉伸反应中分泌的新因子，并确定这些因子对颗粒细胞健康和卵泡生长的影响。这项研究可能为提高牛的生育能力提供新的方法，并可能为其他经历相同类型卵泡生长的物种提供新的方法，包括羊、马和濒危物种。