Model-driven bacterial engineering for complex spheroid environments

活细胞中复杂基因回路的正向工程技术的快速发展，为揭示生命规律和控制生物技术过程奠定了合成生物学的变革潜力。该项目旨在利用并进一步发展不同菌株和种类的细菌对不断变化的环境进行通信和同步响应的能力。我们的多学科方法结合了基因工程、微流体技术和计算方法的进展，设计了新的基因网络，可以利用相关的环境线索在复杂环境中协调细菌种群动态。这个项目的总体目标是在复杂的环境中对细菌电路动力学进行建模、设计和表征。将设计两种新的细菌基因回路系统。第一个是一个远程耦合平台，通过过氧化氢来同步菌落行为。第二种是裂解介导的基因回路系统，可用于调节多菌种生态的共培养。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形环境中新工程电路的知情开发和定量表征。利用这些知识，研究人员将把开发的电路与治疗递送或生物传感菌株结合起来，创建相关的、功能性的合成系统，用于复杂的环境。2011年在美国国家科学基金会支持下启动的“小学科学伙伴计划”将得到扩大。该项目目前服务于圣地亚哥地区的两所一级小学，Ocean Knoll和Lafayette，并包括该地区的聋人和听力障碍者项目。该项目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。该项目将为下一代数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和在复杂的现实世界环境中部署细菌之间的方法学差距。该奖项反映了美国国家科学基金会的法定使命，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.