Genome-Scale in silico Model for E. coli

背景：这个R01项目成立于1998年，引领了细菌代谢基因组尺度重建的发展，特别强调大肠杆菌。这些重建已被广泛传播到研究界，并导致世界各地实验室产生许多科学研究。这些基因组尺度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。计划建议：这个延续计划概述了一个有两个具体目标的计划。第一个目标是继续发展重建技术，扩大目前正在重建的网络的范围，在基因组规模上包括代谢、基因表达的调节，包括双组分信号，以及转录和翻译。这一目标的实现将导致任何生物最大和最全面的网络重建。第二个目标是利用目前全面代表大肠杆菌已知代谢的代谢重建，对大肠杆菌新的代谢能力进行前瞻性的发现。这种发现是通过间隙填充程序完成的，该程序遵循野生型和敲除菌株的高通量表型实验。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：这个项目，如果更新，将继续开拓新的基因组规模的原核细胞科学。它将为类似的人类病原体、对环境有重要意义的生物和对生物恐怖主义有重要意义的生物的分析奠定基础。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.