Systems approach to deciphering molecular mechanisms of infertility in lactating dairy cows with subclinical ketosis

可持续的乳制品生产是奶牛长寿的一个功能。寿命缩短是没有利润的，因为减少终身产奶量，它是环境不可持续的，因为更多的替代小母牛必须保持在牛群中。从根本上说，由于卵巢功能障碍而导致的生殖衰竭是淘汰的首要原因。因此，迫切需要了解卵巢功能障碍的机制，以制定诊断，治疗和管理策略，以优化泌乳奶牛的繁殖性能。长期以来，人们一直认为奶牛在泌乳早期经历的代谢应激会对生殖过程产生负面影响。亚临床酮病（SCK）是奶牛群中最常见的代谢紊乱。我们推测与SCK相关的代谢改变对卵巢卵泡基因表达有独特的影响。该项目的目的是确定代谢和激素水平，并在健康和SCK奶牛的肝脏和卵巢颗粒细胞的基因表达谱。这些目标与我们的行业合作伙伴Novalait的研究重点“奶牛繁殖力和繁殖”保持一致。本研究拟采用系统生物学方法，结合RNA测序技术、分子生物学和生物信息学手段，对健康奶牛和SCK奶牛的肝脏和卵巢功能进行研究。其他分子生物学技术和农场数据，包括生产，营养，繁殖和淘汰率也将被用来联系代谢紊乱卵巢功能障碍。该项目的结果将增强我们对SCK对卵巢功能的影响的理解，从而提高泌乳奶牛的生育力。所产生的数据可能有助于识别牛奶中的标志物集，这将预测患SCK和随后的生殖功能障碍的奶牛。这些标记可用于向农民建议具有潜在生殖问题的奶牛，并需要适当的干预以最好地实现生育和长寿。

Sustainable dairy production is a function of dairy cow longevity. Reduced longevity is not profitable because of reduced lifetime milk yield and it is environmentally unsustainable because more replacement heifers have to be maintained in the herd. Reproductive failure, which is fundamentally due to ovarian dysfunction, is the number one cause of culling. Therefore, understanding the mechanisms of ovarian dysfunction is urgently needed to develop diagnostic, therapeutic and managemental strategies to optimize reproductive performance of lactating dairy cows. The metabolic stress that the cows experience during early lactation has long been proposed to negatively impact reproductive processes. Subclinical ketosis (SCK) is the most prevalent metabolic disorder in dairy herds. We hypothesize that metabolic alterations associated with SCK have unique effects on ovarian follicular gene expression. The objective of this project are to determine metabolic and hormonal levels and to profile gene expression in the liver and ovarian granulosa cells of healthy and SCK cows. These objectives are aligned with the research priority, "Dairy cattle fertility and reproduction" of our industry partner, Novalait. We propose to use systems biology approach employing RNA sequencing technology, molecular biology and bioinformatics tools to investigate the liver and ovarian functions in healthy and SCK cows. Other molecular biology techniques and on-farm data including production, nutritional, reproduction and culling rate will also be used link metabolic perturbation to ovarian dysfunction. The results of this project will enhance our understanding of the impact of SCK on ovarian functions and thus lactating cow fertility. The data generated may contribute to identification of marker sets in milk that will predict cows suffering from SCK and consequent reproductive dysfunction. Such markers could be used to advise farmers of the cows with potential reproductive problems and needing appropriate intervention to best achieve fertility and longevity.