Peri-conceptional stress signalling through O-GlcNAcylation: effects on the early maternal-embryonic interface

通过 O-GlcNAcylation 的围孕期应激信号：对早期母体-胚胎界面的影响

• 批准号: 2454429
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2454429
• 关键词: Peri; conceptional; stress; signalling; through

Cellular stress during the peri-conceptional period, including that caused by assisted reproductive treatment (ART), can lead to early pregnancy loss, reduced gestation or birthweight and altered postnatal growth, with short- (neurodevelopmental delay) and long- (cardiovascular and metabolic disease)-term health consequences. Our previous work shows that the first direct cellular interaction between embryonic trophectoderm and the maternal endometrium, which occurs at implantation, is needed to activate the trophoblast gene networks that initiate invasion and placental development. This indicates that events at early implantation are critically important for placentation and a key determinant of whether fetal demand for oxygen/nutrients can be met later in pregnancy. Here we will use cutting-edge in vitro models of human implantation (human embryos, trophoblast stem cells and endometrial organoids) to examine the effects of a known stress response pathway - GlcNAcylation, a post-translational modification that alters protein function - on implantation.We propose to characterise trophoblast stem cell response to enhanced GlcNAcylation and how such stress affects the generation of trophoblast cell lineages required to build a placenta. We will determine how these responses are influenced by maternal cues by co-culturing embryos or embryo mimics (spheroids of trophoblast stem cells) inside endometrial organoids under conditions that promote or suppress cell-cell interactions. Bioinformatic integration of transcriptomic and phenotypic datasets will reveal the trophoblast cell populations that emerge at the earliest phase of human implantation and determine how an adverse environment affects the balance of trophoblast lineage allocation leading to downstream impacts on fetal development. Modelling the earliest steps of placental development in 3D in vitro represents a significant methodological advance for the field. Information on human blastocyst development and the impact of stress on stem cell populations will provide valuable feedback on human embryo developmental competence and health. Thus industries associated with ART will benefit from knowledge that will facilitate improvements to embryo culture and cryopreservation. Our work towards the development of novel peri-conceptional interventions will ultimately have impact by reducing fetal/child mortality and morbidity and relieving the economic and societal burden associated with obstetric/neonatal care and the management of chronic adult disease.

围受孕期的细胞压力，包括辅助生殖治疗造成的压力，可导致早孕流产、妊娠期或出生体重减少以及出生后生长改变，造成短期（神经发育迟缓）和长期（心血管和代谢疾病）的健康后果。我们以前的工作表明，胚胎滋养外胚层和母体子宫内膜之间的第一次直接细胞相互作用，发生在植入，需要激活滋养层基因网络，启动入侵和胎盘发育。这表明早期着床事件对胎盘形成至关重要，是妊娠后期是否能满足胎儿对氧气/营养需求的关键决定因素。在这里，我们将使用最先进的人体植入体外模型（人胚胎、滋养层干细胞和子宫内膜类器官）来检查已知的应激反应途径-GlcNAc酰化的作用，一种改变蛋白质功能的翻译后修饰我们建议研究滋养层干细胞对增强GlcNAc化的反应，以及这种应激如何影响滋养层细胞谱系的产生，制造胎盘我们将通过在促进或抑制细胞-细胞相互作用的条件下在子宫内膜类器官内共培养胚胎或胚胎模拟物（滋养层干细胞的球体）来确定这些反应如何受到母体线索的影响。转录组和表型数据集的生物信息学整合将揭示在人类植入的最早阶段出现的滋养层细胞群体，并确定不利环境如何影响滋养层谱系分配的平衡，从而导致对胎儿发育的下游影响。在体外3D中模拟胎盘发育的最早阶段代表了该领域的重大方法学进步。关于人类胚泡发育和压力对干细胞群的影响的信息将为人类胚胎发育能力和健康提供有价值的反馈。因此，与ART相关的行业将受益于有助于改进胚胎培养和冷冻保存的知识。我们致力于开发新型围产期干预措施的工作最终将产生影响，降低胎儿/儿童死亡率和发病率，减轻与产科/新生儿护理和慢性成人疾病管理相关的经济和社会负担。