Investigating cellular plasticity in the avian primitive streak

研究鸟类原条细胞的可塑性

• 批准号: BB/N002970/1
• 负责人: Andrea Munsterberg
• 金额: $ 49.97万
• 依托单位: University of East Anglia
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN002970%2F1
• 关键词: Investigating; cellular; plasticity; avian; primitive

THE 'BIG' PICTURE: A fascinating question in biology asks how multicellular organisms arise from a single cell: the fertilized egg. During embryogenesis naïve and still plastic progenitor cells interact with each other, first to form different embryonic layers and to organize the main body axes, and later to build specialized organs with highly differentiated cell types and functions. The cells in an embryo coordinate these complex events by communicating with each other using molecular signalling mechanisms. Cell-cell communication is important throughout the life of an organism, for example for repair after injury or for growth and remodelling. A good example for this is skeletal muscle, a tissue that can regenerate and rebuild itself (after injury or after exercise). This is possible, because there are specialized cells in muscle, but also in other tissues, which can divide when stimulated and make more differentiated cells when needed. These specialized cells are tissue-resident stem cells and they respond to the same communication signals that act in the embryo. We need to understand the detailed intricacies of these signals, as they can have different effects depending on the context in which they act. Defects in signalling mechanisms can be detrimental to an embryo, but they can also lead to diseases in adults such as cancer, when cells "mis-behave" and ignore the signals or respond incorrectly and grow uncontrollably as a result.EXPERIMENTAL MODEL SYSTEM: We have used the early chick embryo, which is very similar in its morphology to early human embryos, and investigated the effects of two important cell-cell signaling pathways. From these studies we know that BMP and WNT signals have different effects in different types of early progenitor cells, depending on the stage of development. We also know that these pathways act via a common transcriptional regulator (SMAD), which can switch other genes 'on' or 'off'. In a "HH stage 3" embryo the signals change how cells migrate, but in a "HH stage 4" embryo the SAME signals have no effect on migration but instead alter the fate of the cells; thus at this later stage the cells respond by changing what they will become. We will use state-of-the-art molecular protocols to identify the genes that are switched on or off by the SMAD-switch in these cell populations. We have experience with these methods in the chick embryo, an accessible experimental system and we have assembled a highly skilled team of researchers to execute this programme of research.WHY IS THIS IMPORTANT? BMP and Wnt signaling are widely used cell communication signals that act in many tissues and organs. We know many of the components of the pathways, but we still do not understand why cellular responses to the (apparently) same trigger vary depending on the context. We now have a well-defined system where the cellular response to the same signals has been characterized and is quite divergent: EITHER cell migration is affected OR cell specification is affected. This gives us the unique opportunity to identify which genes have been switched on or off in the responding cells and provide a deeper mechanistic insight at the molecular level. This is needed in order to fully understand how specialised cells form and how they build functional organs. This is not only relevant in developing embryos, if things go wrong the embryo will not survive or become malformed, but is also relevant for stem cell science and tissue engineering, emerging fields of increasing importance and with significant future potential for medicine and health.SPECIFIC OBJECTIVES: We will capitalize on our recent observations and use our well established model system to (1) identify genes that are differentially expressed in response to BMP and Wnt signaling, and to (2) test the expression and function of these genes in both cell migration and cell specification/differentiation.

“大”图片：生物学中的一个引人入胜的问题询问多细胞生物是如何由单个细胞产生的：受精卵。在胚胎发生期间，幼稚且仍然是塑料祖细胞相互相互作用，首先形成不同的胚胎层并组织主体轴，后来构建具有高度分化的细胞类型和功能的专门器官。胚胎中的细胞通过使用分子信号传导机制相互通信来协调这些复杂事件。细胞 - 细胞通信在生物体的整个生命中都很重要，例如在受伤后修复或生长和重塑。一个很好的例子是骨骼肌，一种可以再生并重建自身的组织（受伤后或运动后）。这是可能的，因为肌肉中有专门的细胞，但在其他时机中也可以在刺激时分裂并在需要时产生更多分化的细胞。这些专门的细胞是组织居住的干细胞，它们响应在胚胎中作用的相同通信信号。我们需要理解这些信号的详细复杂性，因为它们可能会根据其行为的背景而产生不同的影响。信号传导机制中的缺陷可以确定为胚胎，但当细胞“误差”并忽略信号并响应错误并因此而无法控制地成长时，它们也可以导致癌症等疾病。经验模型系统：我们使用了早期的鸡胚胎，在早期的培养基中，人们对人类的教室非常相似，并进行了两种疾病的疾病，并进行了两种效果，并效应了两种效果。从这些研究中，我们知道，根据发育阶段，BMP和WNT信号在不同类型的早期祖细胞中具有不同的作用。我们还知道，这些途径通过常见的转录调节器（SMAD）起作用，该途径可以“ ON”或“ OFF”切换其他基因。在“ HH阶段3”胚胎中，信号会改变细胞的迁移方式，但是在“ HH 4阶段”胚胎中，相同的信号对迁移没有影响，而是改变了细胞的命运。因此，在此阶段，细胞通过改变它们将变为的响应。我们将使用最先进的分子方案来识别这些细胞群体中SMAD-SWITCH打开或关闭的基因。我们在Chick Embryo（一种可访问的实验系统）中具有这些方法的经验，并且我们组建了一个高技能的研究人员来执行这项研究计划。为什么这重要？ BMP和WNT信号传导是在许多组织和器官中作用的广泛使用的细胞通信信号。我们知道途径的许多组成部分，但我们仍然不明白为什么细胞对（显然）相同触发因素的反应因上下文而异。现在，我们有一个明确定义的系统，在该系统中，对相同信号的细胞响应已经表征并相差：细胞迁移受到影响，要么影响细胞规范。这为我们提供了独特的机会，可以确定哪些基因在响应细胞中打开或关闭，并在分子水平上提供更深的机械洞察力。为了充分了解专业单元格的形式以及它们如何构建功能器官，这是必需的。这不仅与开发胚胎有关，如果出现问题，胚胎将无法生存或畸形，而且与干细胞科学和组织工程，越来越重要的新兴领域以及对医学和健康的未来潜力的新兴领域有关。特定的目标：我们将在我们的最新观察和使用良好的模型系统上对（我们的良好的模型系统）进行质疑，并确定了（1）的基因（1）。 （2）测试这些基因在细胞迁移和细胞规范/分化中的表达和功能。