The role of miRNAs in the evolution of mammal implantation.

miRNA 在哺乳动物植入进化中的作用。

• 批准号: BB/X007332/1
• 负责人: Mary O'Connell
• 金额: $ 46.72万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX007332%2F1
• 关键词: role; miRNAs; evolution; mammal; implantation.

About 160 million years ago the common ancestor of therian (marsupials and eutherian) mammals left egg-laying behind and evolved a completely unique system for developing offspring. This new reproductive strategy involved the embryo implanting in the wall of the uterus, a step which is necessary for successful pregnancy in all mammals. The majority of mammal pregnancy loss occurs at this stage, and improving our understanding of the mechanisms involved will have significant impact in human fertility and reproduction and beyond, with livestock management, sustainable agriculture, and conservation efforts for extinction-risk mammals dependent upon successful implantation and pregnancy. Whilst all therian mammals share the requirement for implantation to occur correctly, there are differences between species in terms of precisely when this occurs (e.g. humans at around day 7 but in cows this process takes up to three weeks), what the position of the embryo is within the endometrium, and the morphology of the placenta that subsequently develops. In other words, there are parts of the implantation process that are conserved and there are likely some other parts that are unique to particular mammals. We want to gain molecular level understanding of what controls these similarities and differences in implantation strategy across mammals. Here, we are focussing on a group of small, yet very powerful, molecules called microRNAs that can control (in a dynamic and highly sensitive way) what proteins are made in a cell/organ. The primary mode of operation of microRNAs is to stop a specific target protein being made. There are thousands of known microRNA genes, some are shared between species and some are unique to species. MiRNAs are known to emerge at critical time points in the evolution of novel phenotypes in animals - implicating them in the evolution of novel phenotypes/morphologies e.g. the origin of implantation. We have already made significant progress to meet our goal e.g we know specific miRNAs that are key players in implantation, we know particular proteins that have changed their function at the origin of theria and are expressed in the uterus, we know what is controlling the expression of these miRNAs and we have predicted how the miRNA targets have changed across species. We have also developed the protocols, code, and technologies to enable us to carry out this work. Fortuitously major international efforts to provide genomic resources for large numbers of mammals have completed providing us with unprecedented power to compare patterns across ~240 eutherian mammal species. Dr Forde has used and developed specific types of technology (omics, in vitro models) to help address the question of how the uterine environment and the embryo interact with one another in a number of species including cattle and humans. Dr O'Connell's work has addressed how mammals are related to one another, how the functions of genes change through time and how genomes of species respond and adapt. This proposal marries these two areas of expertise with outstanding resources to address the fundamental question of how regulatory innovations impacted upon the origin and subsequent diversification of implantation strategies in mammals.

大约1.6亿年前，兽目（有袋目和真兽目）哺乳动物的共同祖先放弃了产卵，进化出了一个完全独特的后代发育系统。这种新的生殖策略涉及胚胎植入子宫壁，这是所有哺乳动物成功怀孕的必要步骤。大多数哺乳动物的妊娠丢失发生在这个阶段，提高我们对所涉及机制的理解将对人类生育和生殖及其他方面产生重大影响，牲畜管理，可持续农业和保护依赖于成功植入和妊娠的风险哺乳动物的努力。虽然所有的兽目哺乳动物都需要正确的着床，但物种之间在何时发生（例如人类在第7天左右，但在奶牛中，这个过程需要长达三周），胚胎在子宫内膜中的位置以及随后发育的胎盘形态方面存在差异。换句话说，植入过程中有一些部分是保守的，可能还有一些其他部分是特定哺乳动物所独有的。我们希望从分子水平上了解是什么控制了哺乳动物植入策略的相似性和差异性。在这里，我们专注于一组小而强大的分子，称为microRNA，可以控制（以动态和高度敏感的方式）细胞/器官中产生的蛋白质。microRNA的主要工作模式是阻止特定靶蛋白的产生。已知的microRNA基因有数千种，有些是物种间共有的，有些是物种特有的。已知MiRNA在动物中新表型进化的关键时间点出现-暗示它们参与新表型/形态的进化，例如植入的起源。我们已经取得了重大进展，以实现我们的目标，例如，我们知道特定的miRNAs是植入的关键球员，我们知道特定的蛋白质，已经改变了它们的功能在theria的起源，并在子宫中表达，我们知道是什么控制这些miRNAs的表达，我们已经预测了miRNAs的目标如何在物种之间发生变化。我们还开发了协议、代码和技术，使我们能够开展这项工作。幸运的是，为大量哺乳动物提供基因组资源的重大国际努力已经完成，为我们提供了前所未有的力量来比较约240种真兽目哺乳动物物种的模式。福尔德博士使用并开发了特定类型的技术（组学，体外模型），以帮助解决子宫环境和胚胎如何在包括牛和人类在内的许多物种中相互作用的问题。O 'Connell博士的工作涉及哺乳动物如何相互关联，基因功能如何随时间变化以及物种的基因组如何响应和适应。该提案将这两个专业领域与优秀的资源结合起来，以解决监管创新如何影响哺乳动物植入策略的起源和随后的多样化这一根本问题。