Mechanisms of metabolic signaling to the ovary

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Funds are requested for the initiation of a research program with a long term goal of understanding the mechanisms of nutritional regulation of female reproductive efficiency, with emphasis on ovarian mechanisms. The link between nutritional or metabolic status and reproductive success has long been recognized. From both farm animal and human perspectives, there is a pressing need to understand the mechanisms by which metabolic status of the body affects female reproductive efficiency. The ovarian regulation takes center stage because oocyte, the most significant entity of the process of reproduction, attains maturity to be fertilized within specialized ovarian structures called follicles. Bidirectional communication between oocytes and the surrounding somatic cells known as granulosa cells underpins the process of oocyte maturation and fertility. The overall objectives of the proposed program are: 1. To explore the effects of metabolic hormone signaling on the granulosa cells; 2. to explore the short- and long-term effects of metabolic signaling on a) ovarian follicular dynamics; and b) intracellular metabolic sensor molecules of granulosa cells. For the first objective, we will develop mouse models with granulosa-specific deletion of genes encoding receptors for insulin, insulin-like growth factor-1 and leptin. The KO mice will be analyzed for altered reproductive efficiency and granulosa cell gene expression pattern during follicular growth and ovulation. For the second objective we will use swine model maintained at normal, low and high plane of nutrition. Their ovarian dynamics will be monitored by transrectal ultrasonography through at least four reproductive cycles. This approach enables us to study both short-term and long-term effects of metabolic signaling to the ovary. Over all, the proposed research program uses multi-species and multi-disciplinary approaches to link body metabolic status to ovarian function. The results will be highly significant in terms of furthering our fundamental understanding of nutritional regulation of female fertility