System-level properties of the E. coli metabolic network

描述（由申请人提供）：研究者是西北大学医学院的一名从事学术实践的医生-科学家，主要研究兴趣是系统生物学/功能基因组学，相应的临床兴趣是分子病理学。该机构已经证明了对后基因组生物学及其对医学的影响的坚定承诺，建立了基因组医学中心，这是一个跨学科的研究计划。 申请人的研究兴趣源于认识到离散的生物学功能以及因此各种疾病实体大多不能仅归因于单个分子的功能。 相反，生物系统的鲁棒行为在很大程度上源于其各种构建成分之间的复杂相互作用（即，蜂窝网络）。在这个应用程序中，我们建议进行一个高度集成的程序，我们将在定量方面检查复杂的代谢网络的结构，需要保持细胞的正常功能。请注意，这项研究代表了申请人和理论物理学家之间的独特合作（A. L. Barabasi）和细菌/遗传学家（B. L. Wanner）。 该提案的具体目标如下：（1）我们将定量分析模式生物（如大肠杆菌）复杂代谢和遗传网络的结构和功能活性，（2）我们将研究干扰中央代谢网络中蛋白质水平的影响，以帮助建立模型并测试从这些模型的计算机模拟中演变出来的规则，包括检测它们对靶向突变的耐受性;以及（3）我们将尝试在大肠杆菌生理组的研究中，了解代谢网络中发生的动态变化，以响应不断变化的环境。 了解活细胞的各种代谢网络组件之间的相互作用的原理和代谢网络的通用大规模特征将为基础生物学做出重要贡献，并且还将适用于转化研究，例如抗菌药物靶标识别。

DESCRIPTION (provided by applicant): The investigator is a physician-scientist in academic practice at Northwestern University Medical School with a primary research interest in systems biology/functional genomics and a corresponding clinical interest in Molecular Pathology. This institution has demonstrated a strong commitment to post-genomic biology and its implications to medicine by the establishment of the Center for Genomic Medicine, an inter-disciplinary research initiative. The applicant's research interest stems from the recognition that discrete biological functions, and thus various disease entities, mostly cannot be attributed only to the function of individual molecules. Instead, the robust behavior of biological systems arises to a large extent from complex interactions among its various building constituents (i.e., cellular networks). In this application, we propose to conduct a highly integrated program in which we will examine in quantitative terms the structure of complex metabolic networks that are required to maintain the proper function of a cell. Note that this research represents a unique collaboration between the applicant and a theoretical physicist (A.-L. Barabasi), and a bacteria/geneticist (B. L. Wanner). Specific goals for the proposal are the following: (1) We will analyze in quantitative terms the structure and functional activity of complex metabolic and genetic networks of model organisms, such as Escherichia coli, (2) We will examine the effects of perturbing the levels of proteins in central metabolic networks to aid in model building and to test rules that evolve from computer simulations of these models, including examining their tolerance to targeted mutations; and (3) We will attempt to develop an understanding of the dynamic changes that take place in metabolic networks in response to a changing environment, in studies of the Escherichia coli physiome. Understanding the principles of interactions among various metabolic network components of a living cell and the generic large-scale feature of metabolic networks will provide both an important contribution to basic biology, and will also have applicability to translational research, such as antibacterial drug target identification.