Gonadotropin action in the polycystic ovary

多囊卵巢综合征（PCOS）是女性中最常见的激素紊乱，影响5-10%的育龄妇女，通常首先在青春期表现出来。它是不孕症的主要原因，并导致令人痛苦的皮肤问题（痤疮和不需要的体毛），这对生活质量产生负面影响，通常是明显的抑郁症。PCOS也与长期健康风险有关，特别是在以后的生活中发展2型糖尿病（迟发性或非胰岛素依赖型糖尿病）的风险增加3倍。PCOS女性的不孕症是由于排卵不频繁或不排卵（每月释放一个卵子），通常可以通过适当的治疗选择来纠正，但许多女性仍然不自主地不孕和/或有持续的皮肤问题。遗传因素在PCOS的发展中起着重要作用，但我们仍然不完全了解该综合征的原因。然而，最近的遗传研究数据提供了一些新的线索，这些线索可能涉及卵巢功能异常的关键因素，这些数据补充了我们实验室以前的工作，这些工作证明了控制卵巢的紊乱激素信号的重要性。控制卵巢的两种最重要的生殖激素是促黄体生成激素（LH）和促卵泡激素（FSH），它们由大脑中的脑垂体产生。这些激素与细胞表面上的特定蛋白质（受体）结合，这些蛋白质（受体）培育生长的卵子，确保它们以支持健康卵子生长和排卵的方式行事。在PCOS中，人们认为这些受体可能表现异常，导致卵子停止生长并无法排卵。拟议研究项目的目的是详细研究LH和FSH如何作用于正常和多囊卵巢的这些细胞。我们将特别关注卵巢中识别LH和FSH的受体的功能，以及这些激素一旦与其受体结合，在正常女性和PCOS患者的细胞内发出信号的方式。我们将使用颗粒黄体（GL）细胞，这些细胞是在IVF卵子采集时获得的，通常会被丢弃，因为它们不需要。GL细胞将从个体患者中收集并运送到实验室进行研究。我们对这些研究进行了伦理批准，每个患者都给予了知情同意。一旦进入实验室，我们将以各种方式制备细胞，包括培养72小时。使用包括分析细胞产生的激素（以及参与调节激素产生的基因和蛋白质）以及高分辨率显微镜的技术，我们将研究LH和FSH对GL细胞作用的关键步骤，以及这些步骤在正常和PCOS卵巢之间的差异。我们预计，在未来产生的信息可以直接应用于改善PCOS妇女的生活质量。我们希望发现PCOS的特定生化“指纹”，这将适用于早期诊断（例如，在青春期女孩中有PCOS的早期迹象，但没有明确的诊断），特别是识别那些最有可能出现生育问题或长期并发症的人。重要的是，一旦我们确定了PCOS中功能失调的生化途径，将来就有可能设计和测试有可能靶向这些途径中的关键点以改善功能的药物。我们的研究结果将在科学会议上发表，并准备在该领域的领先科学期刊上发表。申请人在向筹款机构、患者团体以及广播和书面媒体介绍他们的研究方面有着丰富的经验。

Polycystic ovary syndrome (PCOS) is the commonest hormone disorder in women, affecting between 5-10% of women of reproductive age, and typically first manifests itself during adolescence. It is a major cause of infertility and causes distressing skin problems (acne and unwanted body hair) that contribute to a negative impact on quality of life and often, overt depression. PCOS is also associated with risks to long-term health, and, in particular there is a 3-fold increase in the risk of developing type 2 diabetes (late onset, or non insulin-dependent diabetes) in later life. Infertility in women with PCOS is due to infrequent or absent ovulation (monthly release of an egg) and can usually be corrected by appropriate choice of treatment but many women remain involuntarily infertile and/or have persistent skin problems. Genetic factors play a major role in the development of PCOS but we still do not fully understand the cause or causes of the syndrome. Nevertheless, recent data from the genetic studies have provided some new clues about the key factors that might be involved in abnormal function of the ovaries and those data complement previous work in our lab that has demonstrated the importance of disordered hormone signals that control the ovary. The two most important reproductive hormones that control the ovary are luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are produced by the pituitary gland in the brain. These hormones bind to specific proteins (receptors) on the surface of cells that nurture the growing eggs, ensuring that they behave in a way that supports healthy egg growth and ovulation. In PCOS, it is thought that these receptors might behave abnormally, resulting in the egg stopping growing and failing to ovulate. The purpose of the proposed research project is to study in detail how LH and FSH act on these cells from normal and polycystic ovaries. We shall focus, in particular, on the function of the receptors in the ovary that recognize LH and FSH and the way in which these hormones, once bound to their receptors, signal within the cell both in normal women and those with PCOS. We will use granulosa-lutein (GL) cells that are obtained at the time of egg collection for IVF and are normally discarded because they are not needed otherwise. GL cells will be collected from individual patients and transported to the lab for our research protocol. We have ethical approval for these studies and the patients each give informed consent. Once in the laboratory we shall prepare the cells in various ways, including culturing them for up to 72h. Using techniques including analysis of hormones produced by the cells (and the genes and proteins that are involved in regulation of hormone production) as well as high-resolution microscopy, we will examine the key steps involved in the action of LH and FSH on GL cells and how these differ between normal and PCOS ovaries. We anticipate that in future the information generated can be directly applied to improve the quality of life of women with PCOS. We expect to uncover specific biochemical "fingerprints" of PCOS that will be applicable to making an early diagnosis (e.g. in adolescent girls with early signs of PCOS but who do not have a firm diagnosis) and, in particular, to identify those most at risk of problems with fertility or long-term complications. Importantly, once we have identified the biochemical pathways that are dysfunctional in PCOS, it will be possible, in future, to design and test drugs with potential to target key points in these pathways to improve function. Our results will be presented at scientific meetings and prepared for publication in the leading scientific journals in the field. The applicants have extensive experience in talking about their research to fund-raising bodies, to patient groups and to broadcast and written media.