Metabolic signalling to the ovary

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Funds are requested for continuation of an established and productive NSERC-supported research program with the long-term objective of determining the mechanisms of metabolic signaling to the ovary. Incredible success in genetic improvement of milk yield in Canadian dairy herds is also associated with a dramatic increase in involuntary culling rates. The major reason for culling of lactating cows is reproductive problems, with 17-18% of the animals eliminated from herds over last five years. Infertility in lactating cows is attributed to the tremendous metabolic alterations they go through after calving. Thus, there is a need to develop new strategies to optimize fertility in lactating cows, which can be accomplished with enhanced understanding of the pathogenesis of their infertility. The long-term goal of my research program is to understand the mechanisms of metabolic regulation of ovarian function. The objectives for the funding period are to investigate: 1) the differentially regulated granulosa cell transcriptome in lactating dairy cows; 2) the mechanisms of the direct effects of beta-hydroxybutyric acid (BHBA) on bovine granulosa cells in vitro; and 3) the role of Pappa in the ovary using a conditional knockout mouse model. For Objective 1, I propose to use RNA-sequencing technology and bioinformatic tools to compare the transcriptome of ovarian granulosa cells in lactating cows that have metabolic stress and nulliparous heifers that do not have metabolic stress. For Objective 2, primary cultures of granulosa cells will be challenged with BHBA at doses found in heifers and lactating cows to investigate the role of BHBA in epigenetic regulation of granulosa cells gene expression and functions. For Objective 2, we will develop granulosa-specific mouse line lacking Pappa gene, the protease that regulates the insulin-like growth factor (IGF) bioavailability. Extensive phenotyping and molecular studies will provide insights into effects of reduced IGF1 signaling due to lack of Pappa activity on ovarian functions and female fertility. These studies will produce impactful data that are applicable to Canadian dairy cows including global gene expression in granulosa cells of lactating cows, direct targets of the metabolite BHBA and mechanisms of regulation by Pappa protease. In addition, the insights developed through these studies are also applicable to metabolic regulation of the ovary and female fertility in mammals.