Transcription factor dynamics in control of pluripotent cell function and identity

控制多能细胞功能和身份的转录因子动力学

• 批准号: G0901533/1
• 负责人: Ian Chambers
• 金额: $ 133.38万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0901533%2F1
• 关键词: Transcription; factor; dynamics; control; pluripotent

Stem cells attract considerable attention because of their potential to repair damaged or exhausted tissue in patients. There are two properties that define stem cells and that account for their potential utility. First, stem cells can make identical copies of themselves and can do this indefinitely, a process we call self-renewal. Second, stem cells can change their properties and become a specialised type of cell that carries out a particular function in our bodies. Within an organism these two properties of self-renewal and specialisation must be balanced. If too many cells specialise, then the stem cell population may run out. If too many cells self-renew, there may be an insufficient supply of specialised cells to maintain an organisms functionality. How does an organism meet these demands upon its stem cell population? We believe we have uncovered an explanation and want to explore the detailed mechanisms behind our observations. We study a type of stem cell called an embryonic stem (or ES) cell. We study mouse ES cells because they are the most tractable experimentally. We found that all cells in an ES cell population are not the same; some have a greater likelihood of specialising and others a greater likelihood of self-renewing. Unexpectedly we found that these two states could interconvert and the cells that were more likely to specialise could still self-renew and move back into a more niave state. Crucially we were able to determine that these two states could be distinguished by the presence or absence of a particular gene regulator, Nanog. In the proposed work, we will ask how Nanog interacts with other gene regulators throughout the genome to turn genes on or off. We will identify genes that carry out the functions of Nanog. A major part of our work will be to determine the mechanisms that switch the Nanog gene on and off and that are therefore central to the function of the stem cell. We will relate our studies to stem cells from more mature embryos and test the relevance of our findings to the intact embryo.Our studies will deliver a deeper understanding of the switches controlling the behaviour of ES cells. Not only will this be important in learning how to optimally apply ES cells in potentially therapeutic situations but may provide fundamental insights applicable to all stem cells.

干细胞引起了很大的关注，因为它们可能会在患者中修复受损或疲惫的组织。有两种定义干细胞的特性，并解释了它们的潜在效用。首先，干细胞可以制作相同的副本，并可以无限期地做到这一点，这是我们称为自我更新的过程。其次，干细胞可以改变其特性，并成为在我们体内执行特定功能的专业细胞类型。在一个生物体中，必须平衡这两种自我更新和专业化的特性。如果太多的细胞专门为，那么干细胞种群可能会用尽。如果自我更新过多，则可能没有足够的专用细胞供应来维持生物体功能。有机体如何满足这些需求对其干细胞群体？我们相信我们已经发现了一个解释，并希望探索观察结果背后的详细机制。我们研究一种称为胚胎（或ES）细胞的干细胞。我们研究小鼠ES细胞是因为它们是实验最容易触及的。 我们发现ES细胞群中的所有细胞都不相同。有些人的可能性更大，而另一些人则具有更大的自我更新可能性。出乎意料的是，我们发现这两个状态可以互换，更可能专业化的细胞仍然可以自我更新并回到更niave的状态。至关重要的是，我们能够确定这两个状态可以通过特定基因调节剂Nanog的存在或不存在。在拟议的工作中，我们将询问Nanog如何与整个基因组中的其他基因调节剂相互作用，以打开或关闭基因。我们将确定执行Nanog功能的基因。我们工作的主要部分是确定开关和关闭Nanog基因的机制，因此对于干细胞功能至关重要。我们将将研究与来自更成熟的胚胎的干细胞联系起来，并测试我们发现与完整胚胎的相关性。我们的研究将对控制ES细胞行为的开关有更深入的了解。这不仅在学习如何在潜在的治疗情况下最佳地应用ES细胞，而且可以提供适用于所有干细胞的基本见解。