INSPIRE track 1: Asynchronous circuit design principles in the essential regulatory network of Caulobacter Crescentus

该INSPIRE奖的部分资金来自计算机与信息科学与工程理事会计算与通信基础部的软硬件基础项目、生物科学理事会综合有机系统部的发展系统项目以及生物与计算共享原则工作组。每个细胞都包含一个极其复杂的控制系统，其功能对生物体的生存和繁殖至关重要。识别设计原则体现在这个知之甚少的核心调控电路的细胞是这个项目的重点。在许多方面，这种细胞控制系统类似于人类设计的电子系统，尽管它使用生化和遗传反应而不是晶体管作为其底层技术。几十年来，电气工程师已经学会了设计原则，使设计强大，可靠的系统成为可能。这个项目研究细胞控制电路是否利用了这些相同的原理，以及是否有新的原理可以从细胞中学习。这是通过分析控制弯杆菌的基本逻辑来解决的。Caulobacter控制电路类似于异步数字电路，一种不使用全局时钟信号来协调系统的数字设计。设计可靠的异步电路是一项艰巨的工程挑战，人们开发了许多有趣的方法来设计和分析这些电路。该项目绘制了基本的控制电路，它调节了对细胞活力至关重要的过程，使用实验室和计算方法相结合。该研究整合了几种高通量数据的结果，包括核糖体分析、细胞周期各点的RNA-seq数据和ChIP-seq，并将其与计算DNA结合基序搜索相结合。将建立一个连续和离散混合的基本细胞调节系统的数学模型，并构建一个相应的异步数字电路，并使用模型检查软件进行分析。电路结构和模型检查结果用于将现有的异步电路设计概念映射到生物领域，并确定可能通过进化选择的新电路设计方法，这些方法导致活细胞显示出极端的鲁棒性。

This INSPIRE award is partially funded by the Software and Hardware Foundations Program in the Division of Computing and Communication Foundations in the Directorate for Computer and Information Science and Engineering, the Developmental Systems Program in the Division of Integrative Organismal Systems in the Directorate for Biological Sciences, and the Biological and Computing Shared Principles working group. Every cell contains an extremely complex control system for functions essential for survival and reproduction of the organism. Identification of the design principles embodied in this poorly understood core regulatory circuitry of the cell is the focus of this project. In many ways, this cellular control system resembles the electronic systems that humans design, although it uses biochemical and genetic reactions instead of transistors as its underlying technology. Over many decades, electrical engineers have learned design principles that enable the design of robust, reliable systems. This project investigates whether cellular control circuitry makes use of these same principles, and whether there are new principles that can be learned from cells. This is addressed by analysis of the essential logic controlling the bacterium Caulobacter crescentus. Caulobacter control circuitry resembles asynchronous digital circuits, a type of digital design that does not use a global clock signal to coordinate the system. The design of reliable asynchronous circuits is a difficult engineering challenge, and many interesting methods for designing and analyzing these circuits have been developed. This project maps out the essential control circuitry, which regulates the processes that are vital to cell viability, using a combination of laboratory and computational methods. The research integrates results from several types of high-throughput data, including ribosome profiling, RNA-seq data at various points in the cell cycle, and ChIP-seq, and combines that with computational DNA binding motif search. A hybrid continuous and discrete mathematical model will be developed for the essential cell regulatory system, and a homologous asynchronous digital circuit will be constructed and analyzed using model checking software. The circuit structure and model checking results are used to map existing asynchronous circuit design concepts to the biological domain, and to identify new circuit design methods that may have been selected by evolution that lead to the extreme robustness displayed by living cells.