Model-driven bacterial engineering for complex spheroid environments

活细胞中复杂基因电路的正向工程的快速进展，确立了合成生物学在揭示生命规则和控制生物技术过程方面的变革潜力。该项目旨在利用和进一步发展不同菌株和细菌物种的能力，以同步交流和响应不断变化的环境。我们的多学科方法结合了遗传工程，微流体技术和计算方法的进步，设计了新的基因网络，可以使用相关的环境线索在复杂的环境中协调细菌种群动态。该项目的总体目标是在复杂环境中建模，工程和表征细菌回路动力学。将设计两种新的细菌基因电路系统。第一个是通过过氧化氢同步菌落行为的远程耦合平台。第二种是裂解介导的基因回路系统，其可用于调节多菌株生态的共培养。研究人员将开发计算建模和定量测量技术，这将导致来自动物肿瘤的球体环境中新工程电路的知情开发和定量表征。利用这些知识，研究人员将联合收割机开发的电路与治疗输送或生物传感菌株相结合，以创建应用于复杂环境的相关和功能性合成系统。2011年在NSF支持下启动的小学科学合作计划将得到扩大。该计划目前服务于圣地亚哥地区的两所一级小学，海洋诺尔和拉斐特，并包括该地区的聋人和听力障碍计划。该计划由加州大学圣地亚哥分校的学生在调查人员的监督下领导和运行。该项目将为下一代定量生物学家的跨学科培训提供充足的机会。在更广泛的背景下，它将弥合在实验室环境中研究细菌与在复杂的现实环境中部署细菌之间的方法差距。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Rapid advances in the forward engineering of complex gene circuits in living cells has established the transformative potential of synthetic biology for uncovering the rules of life and controlling biotechnological processes. This project aims to harness and further develop the ability of different strains and species of bacteria to communicate and respond synchronously to changing environments. Our multi-disciplinary approach combines advances in genetic engineering, microfluidic technologies, and computational methods to design novel gene networks that can orchestrate bacterial population dynamics in the complex environment using relevant environmental cues. The overall goal of this project is to model, engineer, and characterize bacterial circuit dynamics in the complex environments. Two new bacterial gene circuit systems will be designed. The first is a long-range coupling platform for synchronizing colony behavior through hydrogen peroxide. The second is a system of lysis-mediated gene circuits that can be used to regulate the co-culture of multi- strain ecologies. The investigators will develop computational modeling and quantitative measurement technology that will lead to both informed development and quantitative characterization of newly engineered circuits in spheroid environments derived from animal tumors. Using this knowledge, the researchers will combine developed circuits with therapeutic delivery or biosensing strains to create relevant and functional synthetic systems for application to complex environments. An Elementary School Science Partnership program, which was initiated in 2011 with NSF support, will be expanded. The program currently serves two Title I elementary schools in the San Diego area, Ocean Knoll and Lafayette, and includes the District’s Deaf and Hard of Hearing program. The program is led and run by UC San Diego students under supervision from the investigators. This project will provide ample opportunities for cross-disciplinary training of the next generation of quantitative biologists. In a broader context, it will bridge the methodological gap between the study of bacteria in a lab setting and their deployment in complex real-world environments.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.