Role of glycolysis in mesoderm specification and self-organisation of the anterior posterior axis in the mouse embryo.

怀孕中最重要的事件之一发生在妊娠过程的早期，即胚胎植入母亲的子宫。这一事件对妊娠成功至关重要，据估计，植入失败是导致大约30%的流产的原因。在辅助生殖治疗过程中，这一步骤反复出现的问题被认为是一种称为复发性植入失败的情况，对于希望通过体外受精(IVF)受孕的父母来说，这可能是致命的。从胚胎的角度来看，植入也反映了其发育的一个重要时刻。随着胚胎开始发育和生长，细胞必须以受控的方式彼此不同，以便产生不同细胞类型的全谱。这些不同的早期细胞群也必须以正确的速度生长和扩张，这样才能产生合适的大小和比例的器官。作为发育生物学家，我们知道是什么控制了不同类型细胞的产生，由于这一点始于植入阶段，这是全球许多研究实验室的主要关注焦点。然而，细胞如何摄取正确的营养以扩大这些早期细胞群体的问题研究相对较少。事实上，我们对细胞分化和生长这两个基本过程在早期发育中是如何协调的知之甚少。有必要了解更多，因为早期胚胎提供、吸收和使用营养物质的问题可能对我们更好地了解早期妊娠丢失很重要。此外，这可能会为试管受精诊所的研究人员提供改进的方法，在选择胚胎移植给母亲时评估胚胎的健康状况。细胞如何吸收和使用营养物质是一个高度复杂的过程，使用细胞内多条重叠的代谢途径。这项研究计划将侧重于了解细胞如何在早期胚胎中被称为中胚层的区域特异性地吸收葡萄糖。这一区域后来在成人体内产生了许多组织，包括血液系统、骨骼肌和骨骼的大部分。我们将在一些初步数据的基础上得出一个令人惊讶的结果，即这些细胞的细胞膜上有转运蛋白选择性地吸收葡萄糖。我们将跟踪这种葡萄糖是如何在细胞内被用来为新的细胞成分的产生提供燃料的，这些新的细胞成分对于调节中胚层前体细胞的生长非常重要。与此同时，我们将研究葡萄糖是如何被分解并用于细胞代谢的其他部分的，这些部分与发育信号通路的调节有关。我们非常了解这些信号通路，因为它们被认为对早期发育中多种不同类型的细胞的产生非常重要，特别是早期中胚层。因此，我们将揭示细胞分化和生长调节之间的直接联系。这将产生深远的影响，无论是对早期妊娠丢失发生的情况的更好理解，还是对从干细胞分化和扩增特定类型的细胞及其在再生医学中的应用的实验方案的改进。

One of the most important events in pregnancy occurs early in the process, when the embryo implants into the uterus of the mother. This event it so crucial for pregnancy success, that implantation failure is estimated to be responsible for around 30% of miscarriages. Repeated issues with this step during assisted reproductive therapy is considered as a condition called recurrent implantation failure and can be devasting for parents hoping to conceive through in vitro fertilisation (IVF). From the perspective of the embryo, implantation also reflects an important moment in its development. As embryos begin to develop and grow, cells must be come different from one another in a controlled manner so that the full spectrum of different cell types are generated. These different early cell populations must also grow and expand at the correct rate, so that organs are generated of the correct size and proportion. As developmental biologists, we know a lot about what controls the generation of different cell types, and as this is beginning around the stages of implantation, it is a major focus of many research laboratories across the globe. However, the question of how cells uptake the correct nutrients to expand these early cell populations is relatively understudied. In fact, we know very little of how these two essential processes: cell differentiation and growth, are coordinated in early development. It is essential to know more, as problems in the provision, uptake and usage of nutrients by the early embryo may be important for our better understanding of early pregnancy loss. In addition, it is likely to provide researchers in IVF clinics improved methods to assess the health of embryos in their selection for embryo transfer to the mother.How cells uptake and use nutrients is a highly complicated process, that uses multiple overlapping metabolic pathways inside the cell. This research proposal will focus on understanding how cells specifically uptake glucose in a region of the early embryo called the mesoderm. This region later gives rise to many tissues in the adult body including the blood system, skeletal muscle and much of the skeleton. We will build on some preliminary data showing a surprising result that these cells have transporter proteins on the cell membrane to uptake glucose in a selective manner. We will follow how this glucose is used within the cell to fuel the generation of new cellular components important for regulating the growth of mesoderm progenitors. At the same time, we will look at how glucose is broken down and used in other parts of cellular metabolism linked to the regulation of developmental signalling pathways. We know these signalling pathways very well, as they are known to be important for the generation of multiple distinct cell types in early development, and in particular the early mesoderm. Therefore, we will uncover a direct link between the regulation of cell differentiation and growth. This will have far reaching consequences, both for an improved understanding of what happens in early pregnancy loss and for improving experimental protocols for the differentiation and expansion of specific cell types from stem cells and their use in regenerative medicine.