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.