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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胚胎植入母亲子宫的早期。这一事件对怀孕成功至关重要，据估计，约30%的流产是由于植入失败造成的。在辅助生殖治疗过程中，这一步骤的重复问题被认为是一种称为反复植入失败的情况，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，着床也反映了其发育的一个重要时刻。当胚胎开始发育和生长时，细胞必须以一种受控的方式产生不同的细胞，以便产生各种不同类型的细胞。这些不同的早期细胞群也必须以正确的速度生长和扩大，这样器官才能以正确的大小和比例产生。作为发育生物学家，我们非常了解是什么控制了不同细胞类型的产生，并且由于这是从植入阶段开始的，因此它是全球许多研究实验室的主要焦点。然而，细胞如何摄取正确的营养物质来扩大这些早期细胞群的问题相对来说还没有得到充分的研究。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，摄取和使用营养物质的问题可能对我们更好地理解早期妊娠丢失很重要。此外，它可能为体外受精诊所的研究人员提供改进的方法，以便在选择胚胎移植给母亲时评估胚胎的健康状况。细胞如何摄取和利用营养物质是一个高度复杂的过程，它使用了细胞内多个重叠的代谢途径。这项研究计划将集中于了解细胞如何在早期胚胎的一个被称为中胚层的区域特异性地摄取葡萄糖。这个区域后来产生了成人体内的许多组织，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数据的基础上，显示一个令人惊讶的结果，即这些细胞在细胞膜上有转运蛋白以选择性的方式摄取葡萄糖。我们将跟踪这些葡萄糖是如何在细胞内被使用，以促进对调节中胚层祖细胞生长重要的新细胞成分的产生。与此同时，我们将研究葡萄糖是如何被分解并用于与发育信号通路调节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，既可以提高对早期妊娠丢失的理解，也可以改善干细胞中特定细胞类型的分化和扩增的实验方案，以及它们在再生医学中的应用。