Mechanisms affecting oocyte competence in the bovine model: effect of follicular and maternal aging

影响妊娠成败的最关键时期是前7天。超过95%的卵母细胞（卵子）在授精（受孕）后受精，但只有10-40%的卵母细胞产生胚胎。在早期胚胎发育期间这种高损耗率的原因尚不清楚，但与卵母细胞的内在状态有关。这项研究计划的长期目标是阐明影响卵母细胞发育成可存活胚胎能力的激素、细胞和分子机制。该应用程序是由NSERC资助建立的富有成果的研究线的逻辑延伸。我们开发了牛模型来研究生殖衰老，并记录了牛模型中母体衰老与卵母细胞能力下降有关。我们最近的研究结果表明，当卵泡生长的寿命延长3-4天时，卵母细胞的能力也会受到损害。在这项资助中，我们想要解决基本的生物学问题：卵母细胞功能障碍是如何在体内发生的？因此，本研究的重点是了解卵泡和母体衰老过程中卵母细胞能力丧失的相关机制。我们的总体工作假设是，卵母细胞能力的丧失是由母体和卵泡衰老过程中类似的细胞质事件引起的，而染色体功能障碍是母体衰老所特有的。该资助的具体目标是，确定1)卵泡和母体衰老影响的确切胚胎阶段/事件，2)染色体非断裂和纺锤体缺陷在卵母细胞能力丧失过程中的作用，3)卵母细胞染色体端粒是否随着母体衰老而缩短，4)线粒体在卵母细胞能力丧失中的作用。从研究卵泡和母体衰老的影响中获得的信息具有广泛的临床意义，并且与动物和人类有效辅助生殖技术的发展密切相关。我们预计，拟议工作的发现将允许直接改进现有的牛生殖管理技术，如固定时间人工授精、超排卵和胚胎移植。

The most critical period influencing the success or failure of pregnancy is the first 7 days. More than 95% of oocytes (eggs) become fertilized after insemination (conception) but only 10-40% of them produce embryos. The reason for this high rate of attrition during early embryonic development is unclear, but is associated with the intrinsic status of the oocyte. The long-term objective of this research program is to elucidate the hormonal, cellular and molecular mechanisms that affect an oocyte's ability to develop into a viable embryo. This application is a logical extension of fruitful line of research established with NSERC funding. We developed the bovine model for the study of reproductive aging and documented that maternal aging in the bovine model is associated with a decrease in oocyte competence. Our recent results suggest that oocyte competence is also compromised when the life-span of a growing follicle is prolonged by even 3-4 days. In this grant, we want to address the fundamental biological question: How does oocyte dysfunction occur in vivo? Therefore, the focus of the proposed research is to understand the mechanisms associated with loss of oocyte competence during follicular and maternal aging. Our overall working hypothesis is that the loss of oocyte competence is caused by similar cytoplasmic events during maternal and follicular aging while chromosomal dysfunctions are unique to maternal aging. The specific objectives of this grant are, to determine 1) the precise embryonic stage/event affected by follicular and maternal aging, 2) the role of chromosomal non-disjunctions and spindle defects during loss of oocyte competence, 3) if telomere shortening of oocyte chromosomes occurs with maternal aging and 4) the role of mitochondria in loss of oocyte competence. Information gained from studying the effects of follicular and maternal aging has broad clinical implications and is germane to the development of efficient assisted reproductive techniques for animals and humans. We anticipate that findings from the proposed work will allow direct improvements of existing reproductive management techniques in cattle such as, fixed-time artificial insemination, superovulation and embryo transfer.