QSB: Metabolic Engineering of Quorum Circuitry - A Systems Approach

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The long range goal of this project is to develop a computational formalism, built on stochastic Petri nets (SPN) that will enable accurate and dynamic calculation of all system variables and their variances. In particular, computational models of two Escherichia coli genetic circuits (emergence and decay of heat shock transcription factor, s?32, upon heat shock, and cell-to-cell communication or "quorum sensing") will be constructed, validated, and combined, suggesting the incremental assembly of predictive models that will ultimately predict system-wide behavior. Quorum sensing is known to determine the virulence of Pseudomonas aeruginosa (causative agent for cystic fibrosis), E. coli O157:H7 (Enterohemorrhagic E. coli), and Salmonella typhimurium (food poisoning). The focus is on the identification of signature genes that contribute to the synthesis and perception of autoinducer-2 (the signal molecule for quorum sensing), as well as the interplay between this circuit and the ?s32 circuit. By assembling combined circuits and by creating an optimization formalism that captures the stochastic variance, the Principal Investigators (PIs) will create an approach by which phenotype can be predicted, manipulated, and ultimately optimized. The specific optimization objective for the proposed work is to streamline the synthesis process of biologically active recombinant proteins in E. coli and it provides significant motivation for this work. It is expected that stochastic variance information is important in understanding these circuits. However, the approach is intended to evaluate this assertion at each stage of the work.