Quantitative morphogen analysis of periodic ruga patterning

周期性ruga图案的定量形态发生素分析

• 批准号: BB/J009105/1
• 负责人: Jeremy Green
• 金额: $ 56.46万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ009105%2F1
• 关键词: Quantitative; morphogen; analysis; periodic; ruga

Following the Human Genome Project, we know the sum total of genes available to create and maintain the human body. What is still unknown is which genes are active where and when and how they all operate correctly to do their jobs. The integration of that kind of information into a large circuit diagram or computer programme-like description is referred to as a systems biology approach (by analogy to systems analysis in fields like chemical factory design). This is very difficult to do because huge amounts of data are involved, the places where genes operate have very complicated anatomical structures and the computational methods for putting the data together are still being developed. A particularly neglected aspect of this problem is how genes in different cells switch one another off at a distance via secreted chemicals (morphogens) so that in the embryo during development in the womb the right structures are made in the right places. So far, this has been analysed primarily in fruit flies because they are a much simpler system than mammals and their very early development is particularly simple. This project proposal is to study gene regulation in what we have discovered to be a similarly simple part of mammalian anatomy: the transverse ridges, or "rugae", in the roof of the mouth. Humans have four, mice have eight. Each ruga starts as a stripe of expression of one particular gene and each stripe is alike and parallel. Their characteristic spacing and sequential appearance constitute a one-dimensional "periodic" (i.e. repeating) patterning problem. To solve this patterning problem, we will analyze gene expression and morphogen action in the mouse palate in great detail, focusing on four morphogens that we have already identified as important in making these stripes. This involves staining for specific gene products (RNAs) and using engineered mouse strains whose cells light up fluorescently exactly when and where a particular gene is switched on. Digital imaging will allow these gene signals to be quantified accurately. When put together the data - if sufficiently detailed and quantitative - can be interpreted by so-called "reverse engineering" computational algorithms to work out which genes control which other genes and morphogens (including features such as time-lags, amplifiers and logic switches) so that we understand the circuit diagram and programme that makes development of correct anatomy possible. This simple system then serves as a paradigm for a general understanding of this kind of process. Ultimately, this provides not only rich insight into biological processes but also a route towards tweaking these circuits to enhance repair and regeneration for medical ends.

在人类基因组计划之后，我们知道了创造和维持人体的基因总数。目前尚不清楚的是，哪些基因在何时何地活跃，以及它们如何正确运作以完成其工作。将这种信息整合到大型电路图或类似计算机程序的描述中被称为系统生物学方法（通过类比化学工厂设计等领域的系统分析）。这是非常困难的，因为涉及大量的数据，基因运作的地方具有非常复杂的解剖结构，并且将数据放在一起的计算方法仍在开发中。这个问题的一个特别被忽视的方面是，不同细胞中的基因如何通过分泌的化学物质（形态发生素）在一定距离内相互关闭，以便在子宫发育的胚胎中，在正确的位置形成正确的结构。到目前为止，这主要是在果蝇中分析的，因为它们是一个比哺乳动物简单得多的系统，而且它们的早期发育特别简单。这个项目的建议是研究我们发现的哺乳动物解剖学中类似简单的部分的基因调控：口腔顶部的横向脊，或“皱纹”。人类有四个，老鼠有八个。每一条皱纹都是一个特定基因表达的条纹，每条条纹都是相似和平行的。它们的特征间距和顺序外观构成一维“周期性”（即重复）图案化问题。为了解决这个模式化问题，我们将非常详细地分析小鼠上颚中的基因表达和形态发生素作用，重点是我们已经确定的在形成这些条纹中重要的四种形态发生素。这包括对特定的基因产物（RNA）进行染色，并使用经过工程改造的小鼠品系，这些小鼠品系的细胞在特定基因启动的时间和位置准确地发出荧光。数字成像将允许这些基因信号被精确地量化。当把数据放在一起时-如果足够详细和定量-可以通过所谓的“逆向工程”计算算法来解释，以确定哪些基因控制哪些其他基因和形态发生器（包括时滞，放大器和逻辑开关等特征），以便我们理解电路图和程序，使正确的解剖结构的发展成为可能。然后，这个简单的系统可以作为对这种过程的一般理解的范例。最终，这不仅提供了对生物过程的丰富见解，而且还提供了一条调整这些回路以增强医疗目的的修复和再生的途径。

项目成果

Periodic stripe formation by a Turing mechanism operating at growth zones in the mammalian palate.

• DOI: 10.1038/ng.1090
• 发表时间: 2012-02-19
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Economou, Andrew D.;Ohazama, Atsushi;Porntaveetus, Thantrira;Sharpe, Paul T.;Kondo, Shigeru;Basson, M. Albert;Gritli-Linde, Amel;Cobourne, Martyn T.;Green, Jeremy B. A.
• 通讯作者: Green, Jeremy B. A.

Modelling from the experimental developmental biologists viewpoint.

• DOI: 10.1016/j.semcdb.2014.07.006
• 发表时间: 2014-11
• 期刊: SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
• 影响因子: 7.3
• 作者: Economou, Andrew D.;Green, Jeremy B. A.
• 通讯作者: Green, Jeremy B. A.

Computational biology: Turing's lessons in simplicity

• DOI: 10.1016/j.bpj.2021.08.041
• 发表时间: 2021-10-05
• 期刊: BIOPHYSICAL JOURNAL
• 影响因子: 3.4
• 作者: Green, Jeremy B. A.

Thick and thin fingers point out Turing waves.

• DOI: 10.1186/gb-2013-14-1-101
• 发表时间: 2013-01-24
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Economou AD;Green JB
• 通讯作者: Green JB