IMPC: Essential role of the GPI anchor biosynthesis pathway for early placentation and its impact on heart and brain development

IMPC：GPI 锚定生物合成途径对早期胎盘的重要作用及其对心脏和大脑发育的影响

• 批准号: MR/P026125/1
• 负责人: Myriam Hemberger
• 金额: $ 5.1万
• 依托单位: Babraham Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP026125%2F1
• 关键词: IMPC; Essential; role; GPI; anchor

Normal development of an embryo depends on a functional placenta, which is the organ responsible for all nutrient and oxygen supply to the growing baby during pregnancy. Placental development is tightly coupled to the development of embryonic organ systems. Mouse studies have shown that heart and brain defects in particular are often observed in association with placental failures. In some cases these embryonic pathologies can even be caused solely by the abnormal placenta and, consequently, can be rescued when placental function is restored. Despite this vital function, the importance of the placenta for healthy pregnancy and reproductive success has often been overlooked. In fact our efforts have identified that a far greater number of genes is involved in formation of a functional placenta than has been previously appreciated. In the course of our long-standing interest in this field, we have found that a particular molecular pathway that enables proteins to be anchored to the surface of cell membranes where they may function to recognize and direct specific signals into the cell, plays a pivotal role in placental development. Intriguingly, members of this same biochemical family have been associated in humans with congenital heart defects and neurodevelopmental pathologies resulting in mental retardation, opening up the possibility that these defects may in fact originate in an early placental abnormality. In this work, we will study two components of this pathway to identify their precise role in placental development, using the mouse as a model system. We will investigate very early stages of gestation in which the foundations are laid down for a healthy pregnancy later on, to determine which specific steps in placenta formation are affected. Taking advantage of mouse genetics, we will also study whether the defective placenta is the sole cause of the severe embryonic defects observed. In parallel, using genome editing technology we will establish placental stem cell lines that carry mutations in these factors, which will allow us to elucidate, in the longer term, which particular membrane-bound proteins and which signalling cues are crucial for these developmental processes. This work is of fundamental importance to gain a better understanding of placental development and its impact on formation of key organs in the baby, notably the heart and the brain.

胚胎的正常发育取决于功能性胎盘，胎盘是负责在怀孕期间为生长中的婴儿提供所有营养和氧气的器官。胎盘的发育与胚胎器官系统的发育密切相关。小鼠研究表明，心脏和大脑缺陷通常与胎盘衰竭有关。在某些情况下，这些胚胎病理甚至可以完全由异常胎盘引起，因此，当胎盘功能恢复时，可以挽救。尽管胎盘具有这一重要功能，但它对健康怀孕和生殖成功的重要性常常被忽视。事实上，我们的努力已经确定，更多的基因参与形成一个功能性胎盘比以前已经认识到。在我们对这一领域的长期兴趣中，我们发现一种特殊的分子途径，使蛋白质能够锚定在细胞膜表面，在那里它们可以识别和引导特定信号进入细胞，在胎盘发育中起着关键作用。有趣的是，同一生化家族的成员在人类中与先天性心脏缺陷和导致智力迟钝的神经发育病理学有关，这开辟了这些缺陷实际上可能起源于早期胎盘异常的可能性。在这项工作中，我们将研究这一途径的两个组成部分，以确定它们在胎盘发育中的确切作用，使用小鼠作为模型系统。我们将研究妊娠的早期阶段，为以后的健康妊娠奠定基础，以确定胎盘形成的哪些具体步骤受到影响。利用小鼠遗传学，我们还将研究缺陷胎盘是否是观察到的严重胚胎缺陷的唯一原因。与此同时，利用基因组编辑技术，我们将建立携带这些因子突变的胎盘干细胞系，这将使我们能够从长远来看阐明哪些特定的膜结合蛋白和哪些信号线索对这些发育过程至关重要。这项工作对于更好地了解胎盘发育及其对婴儿关键器官（特别是心脏和大脑）形成的影响至关重要。