Mathematics and Synthesis of a Contact-Mediated Multicellular Patterning System

描述(由申请人提供)：我们建议开发一种新的数学方法来分析接触介导信号的图案形成，并利用结果来设计可编程的多细胞图案系统。这种数学方法将图论思想与动力系统技术相结合，开发出适用于大型细胞网络和广泛类别的接触中介系统的预测和设计模式的系统工具。该方法是用接触图来描述单元的结构，并利用图的对称性将顶点划分成单元的类别 命运是平等的。我们提出了动力系统程序来判断是否存在根据候选划分构造的稳态模式，并揭示其稳定性性质 这样的模式。 为了设计一个合成的细菌接触信号系统，我们建议修改新发现的大肠杆菌接触依赖抑制(CDI)系统，以便我们可以将控制基因表达的蛋白质转移到邻近细胞。接触介导的信号将允许比以前的仲裁信号系统更高的信息含量，因为具有不同功能的整个蛋白质可能被转移。通过在简单的细菌介质中重建模式，该系统将为生物发展中的控制和稳健性理论提供一个试验台。该图案化系统还可能导致在可编程材料、组织工程和隔室生物合成中的应用。 该项目将为接触信号系统生产遗传部件，并为使用这种系统的研究人员提供分析工具包。该团队由木拉提·阿卡克(动力系统和控制理论)、亚当·阿金(合成生物学)和米歇尔·马哈比兹(生物兼容设备)组成，他们目前是合作者，提供必要的数学分析和设计、复杂遗传组件和受控细胞环境方面的专业知识。

DESCRIPTION (provided by applicant): We propose to develop a new mathematical approach to the analysis of pattern formation by contact-mediated signaling and to leverage the results to engineer a programmable multicellular patterning system. The mathematical approach blends graph-theoretic ideas with dynamical systems techniques to develop systematic tools for predicting and designing patterns, applicable to large networks of cells and broad classes of contact-mediated systems. The approach is to describe the configuration of the cells with a contact graph, and to exploit graph symmetries to partition the vertices into classes of cells with equal fates. We propose dynamical systems procedures to determine whether steady-state patterns structured according to candidate partitions exist, and to reveal the stability properties of such patterns. To engineer a synthetic bacterial contact signaling system, we propose to modify the newly discovered E. coli contact-dependent inhibition (CDI) system so that we can transfer proteins that control gene expression to adjacent cells. Contact-mediated signaling would allow higher information content than the previous quorum signaling systems, since whole proteins with different functionality may be transferred. By reestablishing patterning in a simple bacterial medium, this system will provide a testbed for theories of control and robustness in biological development. This patterning system may also lead to applications in programmable materials, tissue engineering, and compartmented biosynthesis. The project will produce both genetic parts for contact signaling systems and an analysis toolkit for researchers employing such systems. The team is composed of Murat Arcak (dynamical systems and control theory), Adam Arkin (synthetic biology), and Michel Maharbiz (biocompatible devices), who are current collaborators and provide the necessary mix of expertise in mathematical analysis and design, complex genetic components, and controlled cellular environments.