Molecular physiology of follicular development and ovulation

在过去的50年里，全球奶牛的繁殖力一直在稳步下降。生育率的下降是加拿大乳品业的一个主要担忧，因为它每年都会导致重大的经济损失。然而，与生育率下降相关的分子机制仍然没有得到充分的研究。虽然与生育率下降相关的原因有很多，但它们通常涉及卵巢和特定基因的良好协调调节。最近，我的实验室首次报道了Janus kinas3(JAK3)和Ankyrin-Repeat and SoCS Box Protein 9(ASB9)在卵巢卵泡中的基本调控。体内实验表明，黄体生成素(LH)在排卵前诱导ASB9的同时，下调卵巢颗粒细胞(GC)中JAK3的表达。然而，JAK3和ASB9信号通路在卵泡生长和排卵中的生物学作用尚不清楚。我们的长期目标是剖析调控牛卵巢功能的分子机制，特别是在奶牛生育力下降的背景下。这项研究的重点将放在影响GC增殖、分化和功能的靶基因的细胞信号上。这些研究将导致获得有关卵巢分子生理学的基础知识，并识别潜在的标记以提高牛的受精率。本研究的目的是揭示JAK3和ASB9在卵巢GC中的确切功能，以及它们在卵泡发育和排卵中的信号转导作用。核心假设是JAK3和ASB9在卵泡生长的后期和排卵中起关键作用，它们的信号转导中断将导致生殖效率下降。我们的理论基础是，确定这些基因在GC中的确切作用机制将导致新的和创新的方法来调节卵巢。我们的具体目标将检验以下假设：1)卵泡生长的最后阶段需要激活GC中的JAK3途径；以及2)黄体生成素诱导ASB9和激活ASB9信号对排卵过程至关重要。完成后，这些研究将揭示新的信号通路和GC功能的调节机制，并增加我们对牛繁殖挑战的理解。这项研究计划是一项重大贡献，因为它将确定调节卵巢活动的JAK3和ASB9的目标蛋白。这是一个创新的研究项目，因为它的目的是研究两个候选基因在GC中的功能以前从未被研究过的信号通路的影响。深入了解GC调控是有影响的，因为可以识别与奶牛生育相关的候选基因，并将其用作健康卵母细胞的分子标记，从而减少乳制品行业的经济损失。

Dairy cows fertility has been declining steadily worldwide for the last fifty years. This decline in fertility is a major concern for the dairy industry in Canada since it results in significant economic losses each year. Yet, the molecular mechanisms associated with fertility decline are still not fully investigated. Although the causes associated with fertility decline are various, they often involve the ovary and a well-coordinated regulation of specific genes. The essential regulation of Janus kinase 3 (JAK3) and Ankyrin-repeat and SOCS Box protein 9 (ASB9) in the ovarian follicle has been recently reported, for the first time, by my laboratory. The luteinizing hormone (LH) downregulates JAK3 in ovarian granulosa cells (GC) while inducing ASB9 prior to ovulation from in vivo experiments. However, the biological roles of JAK3 and ASB9 signaling pathways in follicle growth and ovulation are unknown. Our long-term goal is to dissect the molecular mechanisms that regulate the ovarian function in the bovine species, particularly in the setting of dairy cows declining fertility. The emphasis of this research program will be on the cellular signals of target genes that affect GC proliferation, differentiation and function. These studies will lead to the acquisition of fundamental knowledge regarding the molecular physiology of the ovary and the identification of potential markers to enhance bovine fertility. The objective of this proposal is to uncover the precise functions of JAK3 and ASB9 in ovarian GC and the impacts of their signaling in the developing follicle and ovulation, respectively. The central hypothesis is that JAK3 and ASB9 play pivotal roles in the late stages of follicular growth and in ovulation and that disruption of their signaling would contribute to reproductive efficiency decline. Our rationale is that the identification of the exact mechanisms of action of these genes in GC will lead to new and innovative ways to regulate the ovary. Our specific objectives will test the following hypotheses: 1) Final stages of follicular growth require the activation of JAK3 pathway in GC; and 2) Induction of ASB9 by LH and activation of ASB9 signaling is critical for the ovulation process. Upon completion, these investigations will unveil new signaling pathways and mechanisms of regulation of GC function and increase our understanding of bovine reproductive challenges. This research program is a significant contribution since it will determine target proteins for JAK3 and ASB9 that regulate the ovarian activity. It is an innovative research program since it aims to study the impacts of signaling pathways of two candidate genes whose functions in GC have not been examined before. Insight into GC regulation is impactful as candidate genes associated with dairy cows' fertility can be identified and used as molecular markers for healthy oocytes leading to reduced economic losses for the dairy industry.