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

糖酵解在小鼠胚胎中胚层规范和前后轴自组织中的作用。

基本信息

批准号：
MR/V009192/1
负责人：
Benjamin Steventon
金额：
$ 53.76万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FV009192%2F1
关键词：
Role glycolysis mesoderm specification self

项目摘要

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.

怀孕过程中最重要的事件之一发生在早期，当胚胎植入母亲的子宫时。这一事件对怀孕成功至关重要，据估计，植入失败导致约30%的流产。在辅助生殖治疗期间，这一步骤的重复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）怀孕的父母来说，这可能是毁灭性的。从胚胎的角度来看，植入也反映了其发展的重要时刻。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增，以便产生正确大小和比例的器官。作为发育生物学家，我们知道很多关于是什么控制了不同细胞类型的生成，并且由于这是从植入阶段开始的，因此它是地球仪许多研究实验室的主要焦点。然而，细胞如何吸收正确的营养物质来扩大这些早期细胞群的问题相对来说研究不足。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。了解更多是至关重要的，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，它可能为IVF诊所的研究人员提供改进的方法，以评估胚胎的健康状况，以选择胚胎移植给母亲。细胞如何吸收和使用营养是一个非常复杂的过程，它使用细胞内的多个重叠代谢途径。这项研究计划将集中在了解细胞如何在早期胚胎中称为中胚层的区域特异性摄取葡萄糖。这个区域后来在成人体内产生了许多组织，包括血液系统，骨骼肌和大部分骨骼。我们将建立在一些初步的数据显示一个令人惊讶的结果，这些细胞的细胞膜上的转运蛋白，以选择性的方式摄取葡萄糖。我们将跟踪这种葡萄糖是如何在细胞内使用的燃料的新的细胞成分的产生重要的调节中胚层祖细胞的生长。与此同时，我们将研究葡萄糖如何被分解并用于与发育信号通路调控相关的细胞代谢的其他部分。我们非常了解这些信号通路，因为它们对于早期发育中多种不同细胞类型的产生非常重要，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，无论是为了更好地了解在早期妊娠丢失中发生的事情，还是为了改进从干细胞分化和扩增特定细胞类型及其在再生医学中的应用的实验方案。