NF-kB信号通路的全新设计与合成

The ability to sense environmental signal and make proper decisions is crucial for biology. A number of highly conserved signaling transduction kinase modules evolved to be able to deal with environmental signals with complicated response dynamics. The spatial, temporal and quantitative changes of signaling dynamics determine cell-fate, such as proliferation, differentiation, and apoptosis. Despite that the individual components of these kinase modules have been widely characterized, it is still a major challenge in biological research to fully understand how intracellular molecular components interact to form complex networks that can precisely and dynamically regulate cellular processes. We propose to combine the recent development of systems biology theory with the experimental exploration of synthetic biology approaches to design and resynthesize human nuclear factor-kappa B (NF-kB) signaling cascades in the budding yeast, to ask how to design signaling cascades with desired signaling dynamics, and how these dynamic signals regulate differential downstream gene expression. Such "Learning by Building" strategy could enable us to fully understand the relationship of signaling networks' structure and function. Uncovering these synthetic signaling networks' designing and evolutionary principles, would lead us to further understand the mechanism of signaling network related diseases, and also be able to reprogram natural occurring signaling transduction networks, eventually achieve the ability of the customized signaling cascades design, which could greatly benefit extensive therapeutic purpose and biological industry.

真核细胞进化出多种高度保守的信号转导网络，能够对环境的变化做出非常复杂的动态响应，这些动态响应在时间、空间以及数量上的差异决定着不同的细胞命运。尽管这些信号网络的单个组份已经被广泛研究，但是它们如何组织在一起形成复杂的网络结构，精确的、动态的调控生命过程，仍然是从根本上理解生命系统的关键问题。本项目将运用系统与合成生物学方法，在真核生物酵母细胞内，从头设计合成哺乳动物细胞经典NF-kB信号通路，结合理论计算，研究认识信号通路的构建原理与动力学信号调控机制，发展特定动力学功能信号网络的人工设计方法。这种"以建易学"的研究思路，将帮助我们深入理解信号转导网络的结构与功能的关系。揭示这类网络的设计和进化原理，不仅使我们从根本上理解与这类信号转导网络相关的疾病发生发展的机制，更将赋予我们对天然信号转导网络进行重新设计编程的能力，最终实现客户定制式的信号网络设计合成，并广泛应用到医疗和工业生产中。

真核细胞进化出多种高度保守的信号转导网络，能够对环境的变化做出非常复杂的动态响应，这些动态响应在时间、空间以及数量上的差异决定着不同的细胞命运。尽管这些信号网络的单个组份已经被广泛研究，但是它们如何组织在一起形成复杂的网络结构，精确的、动态的调控生命过程，仍然是从根本上理解生命系统的关键问题。本项目运用系统与合成生物学方法，在真核生物酵母细胞内，从头设计可稳定振荡的NF-kB信号通路。通过与理论计算相结合，系统性研究了网络结构和参数对振荡波形的影响，发现了负反馈对振荡周期的重要调控作用；并发现一种特殊的双层负反馈结构能够实现振荡的频率调控。这种“以建易学”的研究思路，不仅能够帮助我们理解基于信号转导网络的疾病发生机制，同时能够提供对天然信号转导网络进行重新设计编程的能力，最终实现客户定制式的信号网络设计合成。