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通过接触介导的信号传导形成的图案，并利用结果来设计可编程的多细胞图案形成系统。数学方法将图论思想与动力系统技术相结合，开发了用于预测和设计模式的系统工具，适用于大型细胞网络和广泛的接触介导系统。该方法是用接触图描述细胞的结构，并利用图的对称性将顶点划分为细胞类， 命运相同我们提出动力系统的程序来确定是否存在根据候选分区结构的稳态模式，并揭示稳定性 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E。coli接触依赖性抑制（CDI）系统，使我们能够将控制基因表达的蛋白质转移到邻近细胞。接触介导的信号传导将允许比以前的群体信号传导系统更高的信息含量，因为具有不同功能的整个蛋白质可以被转移。通过在简单的细菌培养基中重建图案，该系统将为生物发展中的控制和鲁棒性理论提供测试平台。 这种图案化系统也可能导致在可编程材料、组织工程和区室生物合成中的应用。 该项目将产生接触信号系统的遗传部分和使用此类系统的研究人员的分析工具包。该团队由穆拉特Arcak（动力系统和控制理论），Adam Arkin（合成生物学）和Michel Maharbiz（生物相容性设备）组成，他们是当前的合作者，并提供数学分析和设计，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.