Functional Constraints on the Acquisition of Novel Metabolic Controls

获得新型代谢控制的功能限制

• 批准号: 1517052
• 负责人: James Carothers
• 金额: $ 40.96万
• 依托单位: University of Washington
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1517052&HistoricalAwards=false
• 关键词: Functional; Constraints; Acquisition; Novel; Metabolic

This project addresses a fundamental question about the evolution of the complex systems that are used by organisms to control their essential activities such as gene expression and metabolism (the chemistry of life); To what degree have naturally-occurring control systems evolved to minimize the costs to the organism of operating the control systems themselves? The project will utilize synthetic biology approaches to construct a new metabolic pathway in a bacterium (E. coli) with distinct RNA regulatory mechanisms that can be experimentally authenticated. The research will employ iterative cycles of experiment and computational modeling and will not only provide insight into the benefits and costs of RNA-based regulation, but also serve as a platform for designing more efficient regulatory systems of microbial metabolic processes in biomanufacturing. This project is integrated with a formal teaching program and outreach efforts to inspire more women, underrepresented minority groups, and first-generation college students to consider careers in science and engineering. Workforce training and development will be provided to young career scientists through an interdisciplinary research and education experience in mathematical modeling, computational biology and genetic engineering. High school and incoming college students will be introduced to science and engineering through hosted research experiences that connect familiar real-world problems in energy and medicine to basic concepts in synthetic biology. Investigating functional constraints of metabolic control circuitry is an essential aspect of understanding the design limits that shape the evolution of complex regulatory networks. The goal of this project is to apply synthetic biology approaches (an engineered p-amino-cinnamic acid pathway in E coli) to address the hypothesis that RNA regulatory networks have evolved to minimize the energetic and metabolic costs of the control system itself. This project will integrate computational design space analysis, quantitative RNA device engineering and metabolic pathway construction to investigate the constraints of dynamic RNA-based metabolic control systems. Specifically, this will involve: (1) assessing the cost of acquiring novel metabolic functionality; (2) assessing the cost of acquiring novel RNA-based control functions; and (3) performing model-driven quantitative assessments of metabolic control system functions. This work is expected to shed light on whether RNA-based metabolic control mechanisms in microbes are the result of historical happenstance, are remnants of an RNA World, or whether they might be uniquely suited to provide control with low metabolic burden. These efforts will result in new theoretical and experimental frameworks for both studying and engineering complex metabolic systems that can be used for metabolic engineering purposes.This award is funded jointly by the Systems and Synthetic Biology Program in the Division of Molecular and Cellular Biosciences and the Biomedical Engineering Program in the Division of Chemical, Bioengineering, Environmental and Transport Systems.

该项目解决了一个基本问题，即生物体用来控制其基本活动（如基因表达和代谢（生命的化学））的复杂系统的进化;在何种程度上自然发生的控制系统进化到最小化控制系统本身运行的成本？该项目将利用合成生物学方法在细菌（E。大肠杆菌）具有不同的RNA调控机制，可以通过实验验证。该研究将采用实验和计算建模的迭代循环，不仅将深入了解基于RNA的调控的益处和成本，还将作为设计生物制造中微生物代谢过程更有效调控系统的平台。该项目与正式的教学计划和推广工作相结合，以激励更多的妇女，代表性不足的少数群体和第一代大学生考虑从事科学和工程职业。将通过数学建模、计算生物学和遗传工程方面的跨学科研究和教育经验，向年轻的职业科学家提供劳动力培训和发展。高中生和即将入学的大学生将通过托管研究经验介绍科学和工程，这些经验将能源和医学中熟悉的现实问题与合成生物学的基本概念联系起来。研究代谢控制电路的功能约束是理解复杂调控网络演变的设计限制的一个重要方面。该项目的目标是应用合成生物学方法（大肠杆菌中的工程化p-氨基-肉桂酸途径）来解决RNA调控网络已经进化到最小化控制系统本身的能量和代谢成本的假设。本计画将整合计算设计空间分析、定量RNA装置工程与代谢路径建构，以探讨动态RNA代谢控制系统的限制条件。具体而言，这将涉及：（1）评估获得新的代谢功能的成本;（2）评估获得新的基于RNA的控制功能的成本;以及（3）对代谢控制系统功能进行模型驱动的定量评估。这项工作有望揭示微生物中基于RNA的代谢控制机制是否是历史偶然事件的结果，是RNA世界的残余，或者它们是否可能独特地适合于提供低代谢负担的控制。这些努力将导致新的理论和实验框架，研究和工程复杂的代谢系统，可用于代谢工程的目的。该奖项是由系统和合成生物学计划在分子和细胞生物科学部门和生物医学工程计划在化学，生物工程，环境和运输系统部门联合资助。