Understanding size-robust self-organization of morphogen gradients

了解形态发生素梯度的尺寸稳健自组织

• 批准号: BB/W003619/1
• 负责人: Tom Hiscock
• 金额: $ 48.89万
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW003619%2F1
• 关键词: Understanding; size; robust; self; organization

BACKGROUNDThere is an incredible diversity of biological structures throughout the natural world. These structures are complex yet precise e.g. a human hand must be the correct size and shape, as well as containing cell types (e.g. nerves, muscle, bone) in the right place and the right amounts. Unlike man-made structures, biological structures are not created fully-formed; we all began life as a single cell. Instead, growth, patterning and shape-changes transform a tiny embryo into a complex animal, a process known as development.OVERALL QUESTIONAs an animal or organ develops, it is essential that cells know where they are within it to become the correct cell type and activate the right genes. It has long been known that cells use molecules to measure their location, akin to a molecular GPS. The general idea is that a molecular signal is made in a specialized zone outside the organ (a signalling centre), which then gradually seeps in, forming a concentration gradient. If a cell senses a high concentration, then it knows that it is close to the signalling centre and activates the appropriate genes, and vice versa. However, our understanding of this process has changed dramatically in recent years. Whilst cells do measure their position using molecular gradients, we are finding that these gradients still form if signalling centres, originally thought to be essential, are removed. In other words, cells are not just passively responding to the gradient, they are actively involved in making it, a process that we do not yet fully understand. This would be like a bathtub full of water forming waves without you ever touching it. SPECIFIC QUESTIONHow do the molecular gradients that control development form without external signalling centres?WHY IS IT IMPORTANT?All animals use molecular gradients repeatedly throughout their development; understanding how they form is therefore a question of fundamental importance. This question also has real practical significance. Recently discovered organoids - organs that can be grown outside of the body from human stem cells - show great promise, since they can be used to mimic human disease and pave the way for organ replacement therapies. However current organoids are highly error-prone and often fail to form the molecular gradients necessary for organ development. Our work will identify strategies to reduce these errors and improve the usefulness of organoids to biomedicine. OUR APPROACHWe will combine mathematics and experiments to build quantitative models of molecular gradients and use these models to predict how organoids can be made less error-prone. Just as we need a precise understanding of materials physics to engineer reliable bridges and buildings, we need a quantitative understanding of developmental biology to bio-engineer reliable organs and organoids. OUR PLANSWe will take two complementary approaches. First, we will study in detail an organoid system which already forms gradients reliably. This is one of the earliest gradients to form in animal species, including humans, controlled by a signal called Nodal. We choose to study this in zebrafish embryo organoids (known as pescoids), ideal for quantitative approaches since we can watch the gradients forming in real-time as well as being able to precisely manipulate them, whilst the genes involved are very similar to those in humans. After building an accurate mathematical model of the Nodal gradient, we will use this model to understand why pescoids make gradients so reliably; we expect that the answer lies in how much individual cells are moving around. In parallel, we will study other molecular gradients known to self-organize in a variety of organs/organoids. By building models of many different molecular signals we will ask whether the principles behind robust Nodal gradients also apply to other systems, and therefore identify general engineering principles to reliably make organs outside the body.

在整个自然界中，生物结构的多样性令人难以置信。这些结构复杂而精确，例如人手必须具有正确的大小和形状，以及在正确的位置和正确的数量包含细胞类型（例如神经，肌肉，骨骼）。与人造结构不同，生物结构并不是完全形成的;我们都是从一个细胞开始生命的。相反，生长，模式和形状的变化将一个微小的胚胎转变为一个复杂的动物，这个过程被称为发育。总体问题随着动物或器官的发育，细胞知道它们在其中的位置以成为正确的细胞类型并激活正确的基因是至关重要的。人们早就知道细胞使用分子来测量它们的位置，类似于分子GPS。一般的想法是，分子信号在器官外的专门区域（信号中心）产生，然后逐渐渗入，形成浓度梯度。如果一个细胞感觉到高浓度，那么它就知道它靠近信号中心并激活相应的基因，反之亦然。然而，近年来我们对这一过程的理解发生了巨大变化。虽然细胞确实使用分子梯度来测量它们的位置，但我们发现，如果最初被认为是必不可少的信号中心被移除，这些梯度仍然会形成。换句话说，细胞不仅仅是被动地对梯度做出反应，它们还积极地参与了梯度的形成，这是一个我们还没有完全理解的过程。这就像一个装满水的浴缸在你不碰它的情况下形成波浪。具体问题在没有外部信号中心的情况下，控制发育的分子梯度是如何形成的？为什么它很重要？所有动物在其发育过程中反复使用分子梯度;因此，了解它们如何形成是一个至关重要的问题。这个问题也具有真实的现实意义。最近发现的类器官--可以从人体干细胞中在体外生长的器官--显示出很大的希望，因为它们可以用来模拟人类疾病，为器官替代疗法铺平道路。然而，目前的类器官非常容易出错，并且通常无法形成器官发育所需的分子梯度。我们的工作将确定减少这些错误的策略，并提高类器官对生物医学的有用性。我们的方法我们将联合收割机结合数学和实验来建立分子梯度的定量模型，并使用这些模型来预测如何使类器官更不易出错。正如我们需要精确理解材料物理学来设计可靠的桥梁和建筑物一样，我们需要对发育生物学有定量的了解来生物工程可靠的器官和类器官。我们的计划我们将采取两种互补的方法。首先，我们将详细研究已经可靠地形成梯度的类器官系统。这是包括人类在内的动物物种中最早形成的梯度之一，由一种称为Nodal的信号控制。我们选择在斑马鱼胚胎类器官（称为pescoids）中研究这一点，这是定量方法的理想选择，因为我们可以实时观察梯度形成并能够精确操纵它们，而所涉及的基因与人类非常相似。在建立了Nodal梯度的精确数学模型之后，我们将使用这个模型来理解为什么pescoids如此可靠地制造梯度;我们希望答案在于单个细胞移动了多少。同时，我们将研究已知在各种器官/类器官中自组织的其他分子梯度。通过构建许多不同分子信号的模型，我们将询问稳健的Nodal梯度背后的原理是否也适用于其他系统，从而确定可靠地在体外制造器官的一般工程原理。

项目成果

Self-organized BMP signaling dynamics underlie the development and evolution of digit segmentation patterns in birds and mammals.

• DOI: 10.1073/pnas.2304470121
• 发表时间: 2024-01-09
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Grall, Emmanuelle;Feregrino, Christian;Fischer, Sabrina;De Courten, Aline;Sacher, Fabio;Hiscock, Tom W.;Tschopp, Patrick
• 通讯作者: Tschopp, Patrick