Molecular & cellular response to gonadotropins in superovulation

激素诱导的卵巢刺激，又称超排卵，是体外受精(IVF)、胚胎移植和其他辅助生殖技术的基本程序。虽然家畜卵巢刺激的方法学已经存在多年。然而，不可预测的卵巢反应，就可存活的卵子和胚胎质量而言，仍然是限制辅助生殖技术项目成功的主要因素。尽管这些问题具有直接的经济影响，因为加拿大出口用于动物繁殖的胚胎和药品，每年高达数百万美元。目前的超排卵技术依赖于外源促性腺激素，包括促卵泡激素(FSH)和促黄体生成素(LH)。促性腺激素与发育中的卵泡细胞表面受体结合，并通过导致细胞增殖和卵泡生长的信号转导途径调节生物学活动。最近的一种刺激卵巢的方法涉及到对磷酸二酯酶(PDE)的药理抑制，PDE是一种使细胞内信使失活的酶，该酶介导了促性腺激素的作用。我们建议将非常高效力的重组促性腺激素(超级激动剂)与PDE的药理抑制相结合，将代表一种诱导超数排卵的新方法。我们的目标是开发减少注射促性腺激素的频率的策略，以减轻对潜在捐赠者的处理压力，并降低劳动力成本。减少促性腺激素的数量是有利的，因为高水平与卵母细胞和胚胎质量的降低有关。因此，我们将合成重组促性腺激素激动剂，并结合PDE抑制剂表征它们在卵巢中的反应。通过表征促性腺激素的分子和细胞反应，我们将确定卵巢药物干预的新靶点。新出现的信息将导致开发更好的超排方法，并提高辅助生殖技术应用于养殖猎物和家畜的成功率。

Hormone-induced ovarian stimulation, also termed superovulation, is an essential procedure for in vitro fertilization (IVF), embryo transfer, and other assisted reproductive technologies.  The methodology for ovarian stimulation in domestic animals has been available for many years.  However, the unpredictable ovarian response, in terms of viable eggs and embryo quality, are still the main factors limiting the success of assisted reproductive technology programs.  These problems have direct economic implications, since export of Canadian embryos, and pharmaceutical products for use in animal reproduction, amounts to several million dollars per year.  The current techniques for superovulation rely on the administration of an external source of gonadotropins including follicle stimulating hormone (FSH), and luteinizing hormone (LH).  Gonadotropins bind to cell-surface receptors of the developing follicle, and mediate biological activities through signal transduction pathways leading to cell proliferation and follicular growth.  A more recent approach to stimulate the ovaries involves the pharmacological inhibition of the phosphodiesterases (PDEs), the enzymes that inactivate the intracellular messenger that mediates the effects of the gonadotropins.  We propose that recombinant gonadotropins of very high potency (superagonists), combined with pharmacological inhibition of the PDEs, will represent a novel method to induce superovulation.  We aim to develop strategies to reduce the frequency of gonadotropin injection in order to lower the handling stress on the prospective donor and decrease the labour costs.  Reducing the amount of gonadotropins is advantageous because high levels are associated with a reduction in oocyte and embryo quality.  Therefore, we will synthesize recombinant agonists of the gonadotropins and characterize their responses in the ovary in combination with the PDE inhibitors.  By characterizing molecular and cellular responses to gonadotropins we will identify novel targets for pharmacological interventions in the ovary.  The emerging information will lead to the development of better methods of superovulation and improved rates of success in the application of assisted reproductive technologies to farmed game and domestic animals.