Bilateral BBSRC-FAPESP: Understanding novel conceptus-maternal communication is the key to improving pregnancy outcome in cattle.

双边 BBSRC-FAPESP：了解新概念-母体沟通是改善牛妊娠结局的关键。

• 批准号: BB/R017522/1
• 负责人: Niamh Forde
• 金额: $ 71.16万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR017522%2F1
• 关键词: Bilateral; BBSRC; FAPESP; Understanding; novel

We know that Agriculture and Food security are of critical importance if we are to feed an increasing population with reduced resources. One factor that greatly affects the economic sustainability of both beef and dairy farming is the length of time it takes for either heifers or cows to establish and maintain successful early pregnancy. Increasing fertility in dairy and beef cattle can improve agriculture efficiency with a long term decrease in agriculture impacts worldwide. A major source of pregnancy loss in cattle occurs in the first 3 weeks of pregnancy and the question of when exactly this embryo loss occurs is unknown. What we do know is that successful communication between the embryo and the maternal uterine environment is crucial for successful early pregnancy. There are three key interactions that need to occur 1) the hormone progesterone needs to act on the endometrium (the tissue that lines the inner part of the uterus) to provide a suitable environment to host the embryo, 2) the embryo must undergo a rapid period of growth which is only possible in the uterus i.e. we cannot recapitulate this in the lab and 3) the conceptus must successfully signal its presence to the mother to sustain early pregnancy.Over the last number of years my work has focused on using a specific type of technology to help address the question of how the uterine environment and the conceptus (which is the embryo proper that forms the calf and the extra-embryonic membrane which forms the placenta) interact with one another. The technologies I have use have focused on transcriptomics and proteomics. Instead of investigating how one gene or protein changes in a given condition e.g. in early pregnancy these technologies allow us to investigate how the expression of lots of genes and/or proteins change in early pregnancy. This gives us a much broader picture of what is occurring both during successful early pregnancy, but also when early pregnancy loss occurs. The main focus of my research has been on 1) the role that a specific hormone progesterone plays in providing a good or insufficient uterine environment to promote successful early pregnancy 2) how the maternal environment responds to the conceptus and 3) if we can use these gene or proteins we have identified as interacting between the conceptus and the endometrium to detect successful early pregnancy in a non-invasive sample matrix.More recently my work has identified that key proteins and molecules, packaged in vesicles that can be released from one cell type e.g. the conceptus and alter a different cell type e.g. the endometrium. I have also shown that the way in which these interactions occur may be different when a male conceptus is present compared to a female conceptus.The objectives of the research program are to determine what components of these vesicles are taken up by the endometrium and alter its function. We will also determine how the communication by these vesicles differs between embryos that have different likely hood of pregnancy success (those generated in an animal which are of high quality compared with those generated using assisted reproductive technologies which have less chance of success). We will also examine how male and female conceptuses signal in a different manner to one another. Collectively the results from this work will lead to 1) enhanced understanding of what drives pregnancy success/ embryo loss, 2) novel targets to intervene to prevent embryo loss and 3) markers of successful early pregnancy.

我们知道，如果我们要用减少的资源养活不断增加的人口，农业和粮食安全至关重要。对肉牛和奶牛养殖业的经济可持续性有很大影响的一个因素是小母牛或奶牛建立和维持成功的早期妊娠所需的时间长度。提高奶牛和肉牛的生育率可以提高农业效率，长期减少全球农业影响。牛妊娠丢失的主要来源发生在妊娠的前3周，并且这种胚胎丢失确切发生的时间尚不清楚。我们所知道的是，胚胎和母体子宫环境之间的成功沟通对于成功的早期妊娠至关重要。有三个关键的相互作用需要发生1）激素孕激素需要作用于子宫内膜（子宫内部的组织）提供一个合适的环境来容纳胚胎，2）胚胎必须经历一个快速的生长期，这只有在子宫中才可能，即我们不能在实验室中重演这一点，3）孕体必须成功地向母亲发出信号，以维持早期妊娠。在过去的几年里，我的工作集中在使用一种特定类型的技术，以帮助解决子宫环境和孕体（即形成小牛的胚胎和形成胎盘的胚外膜）相互作用。我使用的技术主要集中在转录组学和蛋白质组学上。而不是研究一个基因或蛋白质在特定条件下如何变化，例如在怀孕早期，这些技术使我们能够研究大量基因和/或蛋白质的表达如何在怀孕早期发生变化。这为我们提供了一个更广泛的画面，既发生在成功的早期妊娠，也发生在早期妊娠丢失时。我的研究的主要重点是1）一个特定的激素孕酮在提供一个良好或不足的子宫环境，以促进成功的早期妊娠中发挥的作用2）母体环境如何对孕体作出反应和3）如果我们可以使用这些基因或蛋白质，我们已经确定为孕体和子宫内膜之间的相互作用，以检测成功的早期妊娠在一个非孕体。侵入性样品基质最近，我的工作已经鉴定了包装在囊泡中的关键蛋白质和分子，所述囊泡可以从一种细胞类型（例如，孕体）释放并改变不同的细胞类型（例如，子宫内膜）。我还表明，当男性孕体与女性孕体存在时，这些相互作用发生的方式可能是不同的。研究计划的目的是确定子宫内膜吸收这些囊泡的哪些成分并改变其功能。我们还将确定这些囊泡的通信如何在具有不同妊娠成功可能性的胚胎之间存在差异（与使用辅助生殖技术产生的胚胎相比，在动物中产生的胚胎具有高质量，而使用辅助生殖技术产生的胚胎成功的机会较少）。我们还将研究男性和女性的概念如何以不同的方式相互传递信号。总的来说，这项工作的结果将导致1）增强对妊娠成功/胚胎丢失的理解，2）干预以防止胚胎丢失的新目标和3）成功早期妊娠的标志物。

项目成果

Endometrium-on-a-chip reveals the endometrial transcriptome, and protein content of secretome are altered by changes in circulating concentrations of insulin and glucose in vitro

子宫内膜芯片揭示子宫内膜转录组，分泌组的蛋白质含量会因体外胰岛素和葡萄糖循环浓度的变化而改变

• DOI: 10.1101/2020.11.03.361774
• 发表时间: 2020
• 作者: De Bem T

Sex-bias in utero alters ovarian reserve but not uterine capacity in female offspring

子宫内的性别偏见会改变女性后代的卵巢储备功能，但不会改变子宫容量

• DOI: 10.1101/2022.07.11.499550
• 发表时间: 2022
• 作者: Geijer-Simpson A

Biosensor capability of the endometrium is mediated in part, by altered miRNA cargo from conceptus-derived extracellular vesicles

子宫内膜的生物传感器能力部分是由来自孕体来源的细胞外囊泡的改变的 miRNA 货物介导的

• DOI: 10.1101/2023.10.27.564369
• 发表时间: 2023
• 作者: De Bem T

Sex bias in utero alters ovarian reserve but not uterine capacity in female offspring†.

• DOI: 10.1093/biolre/ioac208
• 发表时间: 2023-02-13
• 期刊: Biology of reproduction
• 影响因子: 3.6

MicroRNAs emerging coordinate with placental mammals alter pathways in endometrial epithelia important for endometrial function.

• DOI: 10.1016/j.isci.2023.106339
• 发表时间: 2023-04-21
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Hume, Laura;Edge, Jessica C.;Tinning, Haidee;Wang, Dapeng;Taylor, Alysha S.;Ovchinnikov, Vladimir;Geijer-Simpson, Annika, V;Vrljicak, Pavle;Brosens, Jan J.;Lucas, Emma S.;Simpson, Nigel A. B.;Shillito, Jayne;Forbes, Karen;O'Connell, Mary J.;Forde, Niamh
• 通讯作者: Forde, Niamh