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

点击翻译按钮获取中文摘要

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.