Genome-Scale in silico Model for E. coli

描述(申请人提供)：背景：该R01计划成立于1998年，领导了细菌新陈代谢基因组规模重建的发展，特别是对大肠杆菌的研究。这些重建工作已分发给整个研究界，并导致从世界各地的实验室产生了许多科学研究。这些基因组规模的代谢重建被证明是微生物系统生物学研究中的一个共同点。拟议方案：这份续订方案概述了一个具有两个具体目标的方案。第一个目标是继续开发重建技术，并扩大目前正在重建的网络的范围，以包括基因组水平上的新陈代谢、基因表达的调节，包括两组分信号传递以及转录和翻译。这一目标的实现将导致对任何有机体来说最大和最全面的网络重建。第二个目标是利用代谢重建，它现在全面地代表了大肠杆菌中的已知代谢，用于前瞻性地发现大肠杆菌中新的代谢能力。这一发现是通过对野生型和基因敲除菌株进行高通量表型实验后的缺口填补程序完成的。第二个目标是新颖的，代表了系统生物学通过综合计算和实验研究系统地发现新的生物功能的承诺的实现。总体影响：如果该计划得到更新，将继续开创原核细胞新的基因组规模科学。它将为对人类病原体、对环境重要的生物和对生物恐怖主义具有重要意义的生物进行类似的分析奠定基础。因此，这一结果将对细菌的基础研究和应用研究产生影响。

DESCRIPTION (provided by applicant): Background: Established in 1998, this R01 program has led the development of genome-scale reconstructions of bacterial metabolism, with special emphasis on E. coli. These reconstructions have been disseminated to the research community at large and led to the generation of many scientific studies from laboratories around the world. These genome-scale metabolic reconstructions are turning out to be a common denominator in the study of systems biology in microbes. Proposed Program: This continuation proposal outlines a program with two specific aims. The first aim is to continue to develop reconstruction technologies and expand the scope of the networks currently being reconstructed to include, on a genome-scale, metabolism, regulation of gene expression, including two- component signaling, as well as transcription and translation. The fulfillment of this aim will result in the largest and most comprehensive network reconstruction for any organism. The second aim is to use the metabolic reconstruction, which now comprehensively represents known metabolism in E. coli, for prospective discovery of new metabolic capabilities in E. coli. Such discovery is accomplished through a gap filling procedure that follows high-throughput phenotyping experiments of wild-type and knock-out strains. This second aim is novel and represents fulfillment of the promise of systems biology to systematically discover new biological functions through integrative computational and experimental studies. General Impact: This program, if renewed, will continue to pioneer the new genome-scale science of prokaryotic cells. It will lay the foundation for similar analysis of human pathogens, environmentally important organisms and those of bioterrorism importance. The results will thus have an impact on both basic and applied studies of bacteria.