Mechanisms of metabolic signaling to the ovary

基金要求启动一项研究计划，其长期目标是了解女性生殖效率的营养调节机制，重点是卵巢机制。营养或代谢状况与生殖成功之间的联系早已被认识到。从农场动物和人类的角度来看，迫切需要了解身体代谢状态影响女性生殖效率的机制。卵巢调控之所以占据中心位置，是因为生殖过程中最重要的实体卵母细胞在称为卵泡的特殊卵巢结构中达到成熟并受精。卵母细胞与周围的颗粒细胞之间的双向交流是卵母细胞成熟和生育的基础。建议方案的总体目标是：1。探讨代谢激素信号对颗粒细胞的影响；2. 探讨代谢信号对a)卵巢卵泡动力学的短期和长期影响；b)颗粒细胞的胞内代谢传感器分子。对于第一个目标，我们将开发具有颗粒特异性缺失胰岛素、胰岛素样生长因子-1和瘦素受体编码基因的小鼠模型。将分析KO小鼠在卵泡生长和排卵期间生殖效率和颗粒细胞基因表达模式的改变。对于第二个目标，我们将使用维持在正常、低和高营养水平的猪模型。他们的卵巢动态将通过至少四个生殖周期经直肠超声监测。这种方法使我们能够研究代谢信号对卵巢的短期和长期影响。总的来说，拟议的研究计划使用多物种和多学科的方法来将身体代谢状态与卵巢功能联系起来。这一结果将在进一步加深我们对女性生育能力的营养调节的基本理解方面具有重要意义

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