The role of miRNAs in the evolution of mammal implantation.

miRNA 在哺乳动物植入进化中的作用。

基本信息

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.

项目摘要

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，兽类（有袋类和真兽类）哺乳动物的共同祖先放弃了产卵，并进化出了一套完全独特的后代发育系统。这种新的生殖策略涉及将胚胎植入子宫壁，这是所有哺乳动物成功怀孕所必需的步骤。大多数哺乳动物妊娠失败发生在这个阶段，提高我们对所涉及机制的了解将对人类的生育力和生殖及其他方面产生重大影响，牲畜管理、可持续农业和对濒临灭绝的哺乳动物的保护工作都取决于成功植入和怀孕。虽然所有兽类哺乳动物都需要正确植入，但不同物种之间在植入准确时间方面存在差异（例如，人类在第 7 天左右，但在牛中，这个过程需要长达三周的时间）、胚胎的位置位于子宫内膜内，以及随后发育的胎盘的形态。换句话说，植入过程的某些部分是保守的，并且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着哺乳动物植入策略的这些相似性和差异。在这里，我们关注的是一组小但非常强大的分子，称为 microRNA，它们可以（以动态和高度敏感的方式）控制细胞/器官中蛋白质的生成。 microRNA 的主要运作模式是阻止特定靶蛋白的产生。已知的 microRNA 基因有数千个，有些是物种间共有的，有些是物种所独有的。已知 miRNA 会在动物新表型进化的关键时间点出现——这表明它们参与了新表型/形态学的进化，例如动物。植入的起源。我们已经在实现我们的目标方面取得了重大进展，例如，我们知道在植入中起关键作用的特定 miRNA，我们知道在乳腺起源时改变其功能并在子宫中表达的特定蛋白质，我们知道是什么在控制表达我们已经预测了 miRNA 靶点在不同物种之间的变化。我们还开发了协议、代码和技术来使我们能够开展这项工作。幸运的是，国际上为大量哺乳动物提供基因组资源的重大努力已经完成，为我们提供了前所未有的能力来比较约 240 种真兽类哺乳动物的模式。福特博士使用并开发了特定类型的技术（组学、体外模型）来帮助解决子宫环境和胚胎在包括牛和人类在内的许多物种中如何相互作用的问题。奥康奈尔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基因组如何响应和适应。该提案将这两个领域的专业知识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的基本问题。