DIVERSIFICATION OF VERTEBRATE T-CELL FACTOR (TCF) STRUCTURE AND FUNCTION IN EVOLUTION AND DEVELOPMENT

脊椎动物 T 细胞因子 (TCF) 结构和功能在进化和发育中的多样化

• 批准号: BB/S018190/1
• 负责人: Stefan Hoppler
• 金额: $ 65.19万
• 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: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS018190%2F1
• 关键词: DIVERSIFICATION; VERTEBRATE; CELL; FACTOR; TCF

"Nothing in biology makes any sense; except in the light of evolution" is the famous quote by the eminent geneticist Theodosius Dobzhansky about the understanding of biological mechanisms. Here we propose to follow his advice in order to gain unique, novel and fundamental insight into the function of a prominent biological mechanism, called Wnt signalling, which normally regulates embryo formation and regeneration in humans and other animals. We also know that Wnt signalling can contribute to human disease, such as cancer and diabetes, when it is defective or is abnormally activated.Wnt signalling is a molecular pathway that regulates where and when specific genes are switched on during the building of the embryo, and during maintenance and regeneration of some adult body organs, but unfortunately also in human disease. At the end of the Wnt pathway is a molecule called TCF. TCF contacts and controls the 'switch' DNA sequences in genes that are regulated by Wnt signalling; TCF switches these genes on, when Wnt signalling is active and switches them off, where Wnt signalling is silent. In animals without a backbone (invertebrates) there is just one TCF, so that the Wnt-TCF pathway is relatively straightforward. In humans and closely related animals with backbones (vertebrates) there are many TCFs. Here we will investigate whether having several different TCFs enables Wnt signalling to carry out much more diverse roles to help build the bodies of more complex vertebrates and humans. Knowing how the different TCF proteins have different effects on the genes that they control in the embryo is also highly likely to improve our understanding of how they do different things in various diseases, like cancer and diabetes.In this project we will combine information from several vertebrates and closely related invertebrates on the separate genes that make these different TCFs. We will examine and dissect the different and unique roles of the distinct vertebrate TCFs. Because of the prominent role of Wnt signalling in human disease, such as bowel and liver cancer and Type-2 diabetes, many biomedical researchers are interested in studying the role of the Wnt pathway in normal biology and in these diseases, including specifically the role of TCF molecules. However, adopting the powerful comparative approach, as we will do in this project, has not yet been tried. Our approach will provide us with unique novel insights into this important biomedical mechanism for normal embryo formation, and ultimately also human disease.

杰出的遗传学家西奥多斯·多布津斯基（Theodosius Dobzhansky）关于生物学机制的理解，“生物学上的任何一无所有；除了进化之外，除了进化之外，没有任何意义。”在这里，我们建议遵循他的建议，以便获得对一种称为Wnt信号传导的重要生物学机制功能的独特，新颖和基本的见解，该机制通常调节人类和其他动物的胚胎形成和再生。我们还知道，Wnt信号传导可能有助于人类疾病，例如癌症和糖尿病，何时有缺陷或被激活。Wnt信号传导是一种分子途径，在胚胎建立期间，在某些成年身体的维持和再生过程中，但在人类病中，在胚胎构建期间，在胚胎建立和再生过程中开启了特定基因的何时何地和何时打开。在Wnt途径的末端是一种称为TCF的分子。 TCF接触并控制受Wnt信号调节的基因中的“开关” DNA序列；当Wnt信号发导处于活动状态并将其关闭时，TCF打开了这些基因，在Wnt信号是无声的情况下。在没有骨架（无脊椎动物）的动物中，只有一个TCF，因此Wnt-TCF途径相对简单。在人类和与骨干（脊椎动物）密切相关的动物中，有很多TCF。在这里，我们将调查有几个不同的TCF是否使Wnt信号传导能够扮演更加多样化的角色，以帮助建立更复杂的脊椎动物和人类的身体。知道不同的TCF蛋白如何对它们在胚胎中控制的基因产生不同的影响，也很有可能会提高我们对它们在各种疾病中如何做不同事物（例如癌症和糖尿病）的理解。在该项目中，我们将结合几个脊椎动物的信息，并在不同的基因上结合几个脊椎动物的信息，从而使这些不同的TCF与不同的基因相关。我们将检查和剖析不同脊椎动物TCF的不同和独特的作用。由于WNT信号在人类疾病中的重要作用，例如肠和肝癌以及2型糖尿病，许多生物医学研究人员有兴趣研究WNT途径在正常生物学和这些疾病中的作用，包括特定于TCF分子的作用。但是，正如我们将在该项目中采取的强大比较方法，尚未尝试过。我们的方法将为我们提供对正常胚胎形成的这种重要生物医学机制的独特新见解，最终也是人类疾病。

项目成果

Evolutionary diversification of the canonical Wnt signaling effector TCF/LEF in chordates.

• DOI: 10.1111/dgd.12771
• 发表时间: 2022-04
• 期刊: Development, growth & differentiation

A mathematical modelling portrait of Wnt signalling in early vertebrate embryogenesis

早期脊椎动物胚胎发生中 Wnt 信号传导的数学模型

• DOI: 10.48550/arxiv.2203.00779
• 发表时间: 2022
• 作者: Giuraniuc C