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，该功能性胎盘是负责在怀孕期间为生长婴儿提供的所有营养和氧气供应的器官。胎盘发育与胚胎器官系统的开发密切相关。小鼠的研究表明，特别是与胎盘衰竭相关的心脏和大脑缺陷。在某些情况下，这些胚胎病理甚至可能仅由异常胎盘引起，因此，恢复胎盘功能时可以救出。尽管功能至关重要，但胎盘对健康怀孕和生殖成功的重要性经常被忽略。实际上，我们的努力已经确定，与以前所欣赏的基因相比，大量的基因与功能性胎盘的形成有关。在我们对这一领域的长期兴趣的过程中，我们发现，一种可以使蛋白质锚定在细胞膜表面的特定分子途径，它们可以在其中起作用并将特定信号引入细胞中，在胎盘发育中起关键作用。有趣的是，同一生物化学家族的成员与先天性心脏缺陷和神经发育病理的人相关，导致智力低下，这开放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，我们将研究该途径的两个组成部分，以使用小鼠作为模型系统来确定其在胎盘发育中的精确作用。我们将调查妊娠的很早的阶段，在此妊娠中，以后为健康的怀孕奠定了基础，以确定胎盘形成的哪些特定步骤受到影响。利用小鼠遗传学，我们还将研究有缺陷的胎盘是否是观察到严重胚胎缺陷的唯一原因。同时，使用基因组编辑技术，我们将建立胎盘干细胞系在这些因素中带有突变的胎盘干细胞系，这将使我们从长远来看阐明哪种膜结合的蛋白质以及哪些信号线索对于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中关键器官的影响，尤其是心脏和大脑的影响至关重要。