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

不孕症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（ARTs）使不孕症得以治疗，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肥沃的因素。此外，随着女性年龄的增长，卵子的生育能力也会下降。这个问题很重要，因为20世纪后期西方社会的一个主要趋势是推迟生育。这种行为上的改变意味着，越来越多的30多岁至40多岁的女性现在不得不寻求医疗治疗，如体外受精，以克服由于生殖老龄化而导致的非自愿生育。尽管对辅助受孕的需求日益增加，但由于人类卵子很少可供研究，因此研究人类卵子生物学一直非常困难。不幸的是，用于推进科学的方法通常会破坏被研究的细胞。因此，我们对人类卵子生物学的大部分理解都是通过对老鼠卵子的研究拼凑起来的。然而，申请人和其他人最近的发展，一系列高灵敏度的分析意味着现在有可能直接在同一个细胞中测量卵子生物学的多个参数。此外，我们还利用羊等物种开发了动物模型，这可以用来提高我们对人类卵子发育的理解，因为绵羊卵子的生长和成熟方式与人类卵子的生长和成熟过程非常相似。现在的阶段是使用这些创新的工具来测试一个假设，即对人类卵子生物学的详细了解将帮助我们定义人类卵子的健康和生育能力，并更好地理解这些过程是如何随着年龄的增长而改变并导致不孕的。如果我们能在治疗不孕症的过程中发现并生产出质量更好的卵子，我们就能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，并展示这些重要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着年龄的增长而变化。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的发育和生育。卵子和卵泡细胞之间的关系将被研究，卵泡细胞在卵子发育过程中为卵子提供所需的营养。我们确定的最有希望的、新基因的分布和功能意义是卵子发育和生育的调节因子，将在实验室用体外培养的卵子进行测试。在确定了健康女性正常卵子发育的参数后，我们将使用这一标准来衡量随着女性年龄和/或不育，调节卵子质量的开关和机制是如何变化的。最后，我们将利用我们的一系列实验产生的数据来建立人类卵子健康的数学模型。从这些研究中产生的结果将大大提高我们对年轻女性和随着年龄增长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.