Network and topological modelling of transition states in the Wnt signalling pathway.

Wnt 信号通路中过渡态的网络和拓扑建模。

• 批准号: 2596720
• 金额: --
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2596720
• 关键词: Network; topological; modelling; transition; states

Understanding how biological signals are communicated within cells and the complex decision making they support, requires a very precise knowledge of individual pathways and of their role in the wider signalling network. This project will develop and adapt recently developed graph theoretic and topological tools to unravel the complex relationships between different types of Wnt signalling. Wnt signalling is a key pathway that regulates many of the most fundamental cellular processes such as cell expansion and proliferation, cell fate decisions and cell migration. Wnt signalling is dysregulated in many diseases and is often a driver of tumour development. Two related types of Wnt signalling are known, canonical and non-canonical, and whilst both types use many of the same protein components, their functions and activity can be quitedistinct. Several studies have shown that there are complex interrelationships between canonical and noncanonical Wnt signalling , with cells and tissues switching between these modes (Florian et al, Nature, 2013; Upadhyay et al, PLoS Genetics, 2018; Ewing et al, J. Proteome Research, 2018). In this project, we will identify the underlying mechanisms controlling the transitions between these two modes of Wnt signalling by reconstructing the underlying dynamics from experimental observations (single-cell RNA-Seq and bulk gene-expression data). Namely, our project combines network modelling and topology: we superimpose experimental single-cell gene expression data on known regulatory interaction networks to obtain a distance measure that takes into account the directed network structure, and then reconstruct the topology of the underlying dynamical system from these distances. This will allow the identification of transition states between the different signalling modes and to prioritise them for experimental/laboratory study. We will then use wellcharacterized cell-based models of Wnt signalling activity in colorectal cancer (Ewing lab) or in haemopoietic stemcells (Morgan lab) to test and validate the predicted underlying biological mechanisms. The ultimate goal is to develop a fundamental understanding of Wnt signalling and of different modes of Wnt signalling in cancer. Although focused on Wnt signalling, we expect the results of this PhD project to be widely applicable to other biological signalling networks.

了解生物信号如何在细胞内传递以及它们支持的复杂决策，需要非常精确地了解各个途径及其在更广泛的信号网络中的作用。该项目将开发和采用最近开发的图论和拓扑工具来阐明不同类型的 Wnt 信号传导之间的复杂关系。 Wnt 信号传导是调节许多最基本的细胞过程的关键途径，例如细胞扩增和增殖、细胞命运决定和细胞迁移。 Wnt 信号传导在许多疾病中失调，并且通常是肿瘤发展的驱动因素。已知两种相关的 Wnt 信号传导类型，即规范的和非规范的，虽然这两种类型都使用许多相同的蛋白质成分，但它们的功能和活性可能相当不同。多项研究表明，规范和非规范 Wnt 信号传导之间存在复杂的相互关系，细胞和组织在这些模式之间切换（Florian 等人，Nature，2013；Upadhyay 等人，PLoS Genetics，2018；Ewing 等人，J. Proteome Research） ，2018）。在这个项目中，我们将通过实验观察（单细胞 RNA 测序和大量基因表达数据）重建潜在的动态，来确定控制这两种 Wnt 信号传导模式之间转换的潜在机制。也就是说，我们的项目结合了网络建模和拓扑：我们将实验单细胞基因表达数据叠加在已知的调控相互作用网络上，以获得考虑有向网络结构的距离测量，然后从中重建底层动力系统的拓扑距离。这将允许识别不同信号模式之间的过渡状态，并优先考虑它们以进行实验/实验室研究。然后，我们将使用结直肠癌（尤因实验室）或造血干细胞（摩根实验室）中基于细胞的 Wnt 信号传导活性模型来测试和验证预测的潜在生物学机制。最终目标是对 Wnt 信号传导以及癌症中 Wnt 信号传导的不同模式有一个基本的了解。尽管重点关注 Wnt 信号传导，但我们预计该博士项目的结果将广泛适用于其他生物信号传导网络。