Molecular & cellular response to gonadotropins in superovulation

激素诱导的卵巢刺激，也称为超排卵，是体外受精（IVF），胚胎移植和其他辅助生殖技术的基本程序。刺激家畜卵巢的方法已经有很多年了。然而，不可预测的卵巢反应，在活卵和胚胎质量方面，仍然是限制辅助生殖技术项目成功的主要因素。这些问题具有直接的经济影响，因为加拿大胚胎和用于动物繁殖的医药产品的出口每年达数百万美元。目前的超排卵技术依赖于外部促性腺激素的管理，包括促卵泡激素（FSH）和黄体生成素（LH）。促性腺激素与发育中的卵泡细胞表面受体结合，通过信号转导途径介导细胞增殖和卵泡生长的生物活性。最近一种刺激卵巢的方法涉及对磷酸二酯酶（PDEs）的药理学抑制，这种酶使介导促性腺激素作用的细胞内信使失活。我们认为，高效的重组促性腺激素（超级激动剂），结合PDEs的药理抑制，将代表一种诱导超排卵的新方法。我们的目标是制定减少促性腺激素注射频率的策略，以降低潜在供体的处理压力，降低人工成本。减少促性腺激素的数量是有利的，因为高水平的促性腺激素与卵母细胞和胚胎质量的降低有关。因此，我们将合成促性腺激素的重组激动剂，并表征它们与PDE抑制剂联合在卵巢中的反应。通过表征分子和细胞对促性腺激素的反应，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出更好的超排卵方法，并提高将辅助生殖技术应用于养殖野禽和家畜的成功率。

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.