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Modeling regulatory responses to stress in Bacillus subtilis using Petri Net technology This project aims to investigate the use of Petri Nets to model complex bacterial regulatory systems. Developments in post-genomic technology are providing genome wide data enabling the holistic modelling of complex cellular regulatory systems. In particular gene-expression arrays and new proteomics techniques are producing large datasets from studies of molecular processes. New approaches to the analysis of genome-wide data are required to allow data driven models for hypothesis generation, in silico data modelling and simulation to be generated. B. subtilis represents an excellent model organism in which to study global regulatory networks of bacteria. B. subtilis is one of the most genetically amenable and intensively studied bacteria. The entire genome sequence was determined in 1997 (partly by us) and consortium for the systematic analysis of the function of unknown B. subtilis genes has generated a collection distinct integrational, reporter gene mutants in all genes of unknown function, a unique biological resource. With funding from the BBSRC (PRES Initiative), 2 BBSRC Studentships and EU FW5 (Quality of Life), Newcastle is coordinator of a consortium of 10 European laboratories with the primary objective of defining the global regulatory networks of B. subtilis. The regulatory networks group at Newcastle (Prof. Harwood, Dr. Wipat, Dr. Ward and Dr. Glassey) have established an extensive knowledge base that describes complex regulatory mechanisms that occur in this model Gram-positive microorganism in response to phosphate and energy stress. Phosphate starvation is sensed via a two component regulatory system primarily mediated by PhoPR whilst the general stress response regulon is mediated by the sigma factor, B. This project will investigate the use of Petri Nets as a new computational method to model the phosphate response regulon in B. subtilis and to characterise its interplay with the general stress (sigma B) response regulon. Data will be drawn from our laboratory based studies of the transcriptome, proteome and phosphoproteome. Petri Nets are a formal modelling technique based on using simple graph-like structures to represent complex distributed interactions. They were originally developed for modelling and reasoning about complex distributed computing applications, and have the important advantage of being supported by a wide range of analysis tools (such as those based on model checking). Petri Nets lend themselves (particularly stochastic and coloured Petri Nets) to representing the kinds of relations and interconnections that occur in metabolic/regulatory networks, and thus provide a formal means of documenting and analysing the complex relationships that exist between genes, substrates and proteins. Newcastle is a leading international centre for research on Petri Nets, as exemplified by it recently hosting the prestigious Petri Net Conference: Applications and Theory of Petri Nets’2001. In key EPSRC funded projects, researchers are considering both the theoretical foundations (such as problems of compositionality, time Petri Nets, analysis tools) and practical applications (such as VLSI circuit design and programming language development) of Petri Net techniques.