Identifying sperm-egg receptor pairs essential for mammalian fertilization to select new targets for fertility treatment and contraception.

识别哺乳动物受精所必需的精卵受体对，以选择生育治疗和避孕的新靶标。

• 批准号: MR/M012468/1
• 负责人: Gavin Wright
• 金额: $ 44.6万
• 依托单位: Wellcome Sanger Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM012468%2F1
• 关键词: Identifying; sperm; egg; receptor; pairs

In humans and many other organisms, new life starts when a sperm and an egg recognise each other and permit the fusion of the membranes that surround them to form an embryo in a process we call fertilization. The way in which sperm and egg are able to recognise each other is very likely to involve a pair of recognition molecules: one displayed on the surface of the sperm and the other on the egg's surface that specifically bind to each other and finally enable the sperm and egg to fuse and create a genetically distinct embryo. Despite the fact that fertilization is a fundamental biological process our current molecular understanding is remarkably poor, particularly in mammals. This can be partly explained in humans due to the ethical issues involved, but there are also significant technical challenges that make working with sperm and eggs and the molecules on their surface in the laboratory very difficult. For example, eggs are a very rare cell type in mammals (humans usually release just a single egg each fertility cycle and mice less than ten) limiting the amount of biological material available. In addition, the interactions between cell surface recognition molecules are known to be extremely weak (often having half-lives of just fractions of a second), requiring the use of specialised approaches to detect them. The Cell Surface Signalling Laboratory at the Sanger Institute specialises in identifying these transient receptor interactions and we have developed a set of tools and techniques to circumvent these difficulties. We have recently shown, by identifying the first essential sperm-egg receptor pair (see Bianchi et al. Nature 2014 v508 p483), that applying these techniques can make important discoveries in this field. In this grant application, we propose to apply the same techniques in a systematic manner to identify additional sperm-egg recognition molecules but also begin to apply these findings to reveal new targets for fertility treatment and contraceptives. Identifying the cell surface receptors that are important for fertilization could have significant implications for the development of novel contraceptives and fertility treatments. For example, identifying which receptors are required for fertilization and how they interact could provide the starting point to develop new drugs that specifically block the interaction and therefore be used as a contraceptive. Perhaps surprisingly, no new contraceptives have been developed for over 40 years. The rapidly expanding human population (currently over 7 billion and predicted to reach 10 billion by 2050) has raised concerns globally that the limited resources on the planet will not sustain such a continued expansion. A drug that blocks the interaction between sperm and egg could conceivably be taken by both men and women and be effective for just a short period of time (a few hours to several days). It is also likely that the receptor interaction will be used by other animal species and so could be used to design methods to effectively control animal populations in a humane way.Finally, our previous work has shown that interactions between sperm and egg receptors can be essential for fertilization and so our planned research may reveal the identity of new infertility genes. Infertility is a growing problem, particularly in Western countries where the average age of couples having their first child has increased in recent years. By discovering new infertility genes, this research could open up the possibility of offering simple and inexpensive genetic screening tests to infertile couples that may guide their fertility treatment and save the expense and inconvenience of failed rounds of fertility treatment. In addition, by providing a molecular explanation for infertility, this may suggest methods of clinical intervention to help couples conceive.

在人类和许多其他生物中，当精子和卵子相互识别并允许围绕它们的膜融合形成胚胎时，新的生命就开始了，这个过程我们称之为受精。精子和卵子能够相互识别的方式很可能涉及到一对识别分子：一个显示在精子表面，另一个显示在卵子表面，它们专门相互结合，最终使精子和卵子融合并产生基因上不同的胚胎。尽管事实上受精是一个基本的生物过程，但我们目前对分子的了解非常少，特别是在哺乳动物中。由于涉及伦理问题，这在人类中可以部分解释，但也存在重大的技术挑战，使得在实验室中处理精子和卵子及其表面分子非常困难。例如，卵子在哺乳动物中是一种非常罕见的细胞类型（人类通常在每个生育周期只释放一个卵子，老鼠则少于十个），这限制了可用生物材料的数量。此外，已知细胞表面识别分子之间的相互作用极其微弱（通常只有几分之一秒的半衰期），需要使用专门的方法来检测它们。桑格研究所的细胞表面信号实验室专门研究识别这些瞬时受体相互作用，我们已经开发了一套工具和技术来规避这些困难。我们最近发现，通过鉴定第一对必要的精子-卵子受体（见Bianchi等人）。Nature 2014 v508 p483)，应用这些技术可以在这一领域取得重要发现。在这项拨款申请中，我们建议以系统的方式应用相同的技术来识别额外的精子-卵子识别分子，同时也开始应用这些发现来揭示生育治疗和避孕的新靶点。确定对受精有重要作用的细胞表面受体可能对开发新型避孕药具和生育治疗具有重要意义。例如，确定哪些受体是受精所必需的，以及它们如何相互作用，可以为开发专门阻断相互作用的新药提供起点，从而用作避孕措施。也许令人惊讶的是，40多年来没有开发出新的避孕方法。快速增长的人口（目前超过70亿，预计到2050年将达到100亿）引起了全球的关注，地球上有限的资源将无法维持这种持续的扩张。可以想象，一种阻断精子和卵子相互作用的药物，男女都可以服用，而且只在短时间内有效（几小时到几天）。受体相互作用也有可能被其他动物物种使用，因此可以用来设计以人道的方式有效控制动物种群的方法。最后，我们之前的工作已经表明，精子和卵子受体之间的相互作用对受精至关重要，因此我们计划的研究可能会揭示新的不育基因的身份。不孕不育是一个日益严重的问题，特别是在西方国家，近年来，夫妇生第一个孩子的平均年龄有所增加。通过发现新的不育基因，这项研究可以为不育夫妇提供简单而廉价的基因筛查测试，从而指导他们的生育治疗，节省生育治疗失败的费用和不便。此外，通过提供不孕症的分子解释，这可能为临床干预方法提供建议，以帮助夫妇怀孕。

项目成果

Control of oviductal fluid flow by the G-protein coupled receptor Adgrd1 is essential for murine embryo transit.

• DOI: 10.1038/s41467-021-21512-w
• 发表时间: 2021-02-23
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Bianchi E;Sun Y;Almansa-Ordonez A;Woods M;Goulding D;Martinez-Martin N;Wright GJ
• 通讯作者: Wright GJ

Mammalian fertilization: Does sperm IZUMO1 mediate fusion as well as adhesion?

哺乳动物受精：精子Izumo1是否介导融合和粘附？

• DOI: 10.1083/jcb.202301035
• 发表时间: 2023-02-06
• 期刊: The Journal of cell biology

Cross-species fertilization: the hamster egg receptor, Juno, binds the human sperm ligand, Izumo1.

• DOI: 10.1098/rstb.2014.0101
• 发表时间: 2015-02-05
• 期刊: Philosophical transactions of the Royal Society of London. Series B, Biological sciences
• 作者: Bianchi E;Wright GJ
• 通讯作者: Wright GJ

Same gene, opposite sexes: Sex-specific divergent expression of a gene required for vertebrate fertilization.

• DOI: 10.1073/pnas.2116001118
• 发表时间: 2021-10-19
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Bianchi E

Find and fuse: Unsolved mysteries in sperm-egg recognition.

• DOI: 10.1371/journal.pbio.3000953
• 发表时间: 2020-11
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Bianchi E;Wright GJ
• 通讯作者: Wright GJ