CAREER: An Integrated, Metabolomics-based Method for Metabolic Engineering

理解和控制细胞代谢对于从工业生物合成到生物能源生产的应用至关重要，但由于有关代谢动力学和调节的信息有限而受到严重阻碍。这个CAREER项目旨在使用计算驱动的方法来工程化细胞，以产生有价值的化学物质，这些化学物质来自细胞内代谢物水平的细胞范围测量。为了实现这一目标，将开发一种新的代谢模型，包括调节，并以迭代实验/计算方式用于优化酵母酿酒酵母和S. miktek。这项工作将是同类工作中第一个直接使用全细胞代谢物测量来推动代谢工程的工作。该项目的成功完成将有助于重新关注代谢工程的合理设计，并扩大可生物合成生产的化学品的范围。更广泛的影响该项目有可能实现更高效和有效的代谢工程，其应用范围从低成本生产发展中国家负担得起的有用化学品，影响数百万人的生活质量，促进经济上可行的可持续能源生物燃料生产。此外，将为多个物种构建的模型可以帮助阐明代谢进化的机制。该项目的综合研究和教育计划旨在培养儿童的量化、全系统思维，并鼓励代表性不足的群体参与工程学。为此，将在当地社会经济弱势和以少数民族为主的学校实施促进这种心态的现有教育方案。此外，还将在当地一所高中组建一个合成生物学小组，以激发对系统生物学、合成生物学和生物工程的兴趣，并有针对性地招募女性（工程专业人数不足）。

Intellectual MeritUnderstanding and controlling cellular metabolism is crucial to applications ranging from industrial biosynthesis to bioenergy production, but is significantly hindered by limited information about the dynamics and regulation of metabolism. This CAREER project aims to use a computationally-driven approach to engineering cells to produce valuable chemicals, to be derived from cell-wide measurements of metabolite levels within the cell. To achieve this, a new metabolic model that includes regulation will be developed and used in an iterative experimental/computational manner for optimizing production of the valuable chemical succinic acid in the yeasts Saccharomyces cerevisiae and S. mikatae. This work will be the first of its kind to directly use cell-wide measurements of metabolites to drive metabolic engineering. Its successful completion will support the refocusing on rational design in metabolic engineering, and also increase the scope of chemicals that could be produced biosynthetically.Broader ImpactThis project has the potential to enable more efficient and effective engineering of metabolism, with applications ranging from the low-cost production of useful chemicals that become affordable to developing countries, impacting the quality of life for millions of people, to the facilitation of economically feasible production of biofuels for sustainable energy. Additionally, models that will be constructed for multiple species could help elucidate mechanisms of metabolic evolution. The integrated research and education plan of this project seeks to foster quantitative, whole system-level thinking in children, and to encourage the participation of underrepresented groups in engineering. To do so, existing educational programs that promote this mindset will be implemented in local socioeconomically-disadvantaged and predominantly minority schools. Also, a synthetic biology team will be assembled at a local high school to stimulate interest in systems biology, synthetic biology, and bioengineering, with targeted recruitment of females (underrepresented in engineering).