The Life Cycle And Legacy of Human Oocytes In Health, Age and Infertility

不孕不育是人类的一个主要问题，每6对夫妇中就有1对受到影响。虽然辅助生殖技术（ART）使不孕症得到治疗，但体外受精（IVF）和相关技术仍然相对低效和昂贵。这些低成功率的主要原因之一是卵母细胞（卵子）质量差，因为我们对卵子发育的生物学知之甚少，我们不知道使卵子健康和生育的因素的身份。此外，随着女性年龄的增长，卵子的生育能力下降。这个问题很重要，因为西方社会在世纪后期的一个主要趋势是推迟生育。这种行为的变化意味着越来越多的30多岁的妇女现在不得不寻求试管婴儿等医疗，以克服由于生殖老化而发生的非自愿无子女现象。尽管对辅助受孕的需求越来越大，但历史上研究人类卵子生物学非常困难，因为人类卵子很少用于研究。不幸的是，用于推进科学的方法通常会破坏正在研究的细胞。因此，我们对人类卵子生物学的大部分理解都是从对小鼠卵子的研究中拼凑起来的。然而，申请人和其他人最近开发了一系列高灵敏度测定，这意味着现在可以直接在同一细胞中测量卵子生物学的多个参数。此外，我们已经开发了使用绵羊等物种的动物模型，这些动物模型可用于促进我们对人类卵子发育的理解，因为绵羊卵子以一种密切模仿人类相同过程的方式生长和成熟。现在的阶段是使用这些创新工具来测试假设，即对人类卵子生物学的详细了解将有助于我们定义人类卵子的健康和生育能力，并更好地了解这些过程如何随着年龄的增长而改变并导致不育。如果我们能够在不孕症治疗过程中识别并产生更好质量的卵子，我们就能够提高辅助受孕治疗的成功率。拟议的研究方案将通过研究人类和动物的卵子和卵巢细胞来解决这些重要问题。这项研究将测量鸡蛋的营养需求，并显示这些重要的细胞在发育过程中如何利用能量和蛋白质，以及鸡蛋的新陈代谢如何随年龄变化。我们将研究人类和动物卵子的分子和代谢机制的关键组成部分，以便我们能够确定哪些基因，开关和机制调节卵子发育和生育力。将研究卵子及其支持卵泡细胞之间的关系，卵泡细胞在卵子发育过程中为卵子提供所需的营养。我们确定的最有前途的新基因的分布和功能意义将在实验室中使用体外培养的卵子进行测试，这些基因是卵子发育和生育力的调节因子。在确定了健康女性正常卵子发育的参数后，我们将使用这个标准来测量调节卵子质量的开关和机制如何随着女性年龄的增长和/或不孕而变化。最后，我们将使用我们一系列实验产生的数据来建立人类卵子健康的数学模型。这些研究产生的结果将大大促进我们对年轻女性和女性年龄的人类卵子生物学的理解。这项研究的结果将有助于提高辅助受孕治疗的效率和妇女生殖健康的长期管理。

Infertility is a major problem in humans which affects 1 in 6 couples. While assisted reproductive technologies (ARTs) have enabled infertility to be treated, in vitro fertilisation (IVF) and associated technologies remain relatively inefficient and costly. One of the main reasons for these low success rates is poor oocyte (egg) quality, as we know very little about the biology of egg development and we do not know the identity of factor(s) which make eggs healthy and fertile. Furthermore, egg fertility declines as women get older. This issue is important as a major trend in western societies in the late 20th century has been the postponement of childbearing. This change in behavior means that an increasing number of women in their mid to late 30s now have to seek medical treatment such as IVF to overcome the involuntary childlessness which occurs as a result of reproductive ageing. Despite the increasing need for assisted conception, it has historically been very difficult to study human egg biology as human eggs are rarely available for research. Unfortunately, the methods used to advance the science usually destroys the cells being studied. Much of our understanding of human egg biology has therefore been pieced together from studies of mouse eggs. However, the recent development by the applicants and others, of a series of highly sensitive assays means that is it now possible to measure multiple parameters of egg biology directly in the same cell. Further, we have developed animal models using species such as sheep which can be used to advance our understanding of human egg development as sheep eggs grow and mature in a way that closely mimics the same processes in humans. The stage is now set to use these innovative tools to test the hypothesis that a detailed insight into human egg biology will help us to define human egg health and fertility and to better understand how these process can be altered with age and lead to infertility. If we can identify and produce better quality eggs during infertility treatments, we may be able to increase the success of assisted conception treatments. The proposed programme of research will address these important issues by studying human and animals eggs and ovarian cells. The research will measure the nutrients requirements of eggs and show how these important cells utilise energy and protein as they develop and how egg metabolism changes with age. We will study key components of the molecular and metabolic machinery of human and animal eggs so that we can identify which genes, switches and mechanisms regulate egg development and fertility. The relationship between the eggs and their supporting ovarian follicle cells, which provide eggs with the required nutrients throughout their development, will be investigated. The distribution and functional significance of the most promising, novel genes we identify as regulators of egg development and fertility will be tested in the laboratory using eggs grown in vitro. Having established the parameters of normal egg development in healthy women we will use this yardstick to measure how the switches and mechanisms regulating egg quality change as women age and/or become infertile. Finally, we will use the data generated from our series of experiments to build a mathematical model of human egg health. The results generated from these studies will significantly advance our understanding of human egg biology in young women and as women age. The outcome of this research will help improve the efficiency of assisted conception treatments and the long-term management of womens' reproductive health.