Integrated Dynamics of Temporal and Spatial Controls in the Cell Division of Caulobacter crescentus

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The purpose of this project is to gain deeper insight into the molecular mechanisms controlling the growth, division and differentiation of bacteria by building mathematical models of gene expression and protein localization within a bacterial cell. The free-living aquatic bacterium, Caulobacter crescentus, is a suitable organism for addressing such questions because it divides asymmetrically into two different types of cells (a stalked cell and a swarmer cell) and because the molecular basis of its asymmetric division process is easily studied in the laboratory by modern genetic, biochemical and microscopic methods. In light of the wealth of experimental results now available on the genes and proteins controlling this process, the funded project will address the pressing need for accurate and predictive mathematical models that connect detailed molecular mechanisms with the observed properties of Caulobacter reproduction and differentiation. Two types of mathematical models will be considered. Deterministic models--based on systems of nonlinear partial differential equations--will be used to describe the average behavior of a population of Caulobacter cells, which is the type of data collected in many experimental protocols. Stochastic models--based on the reaction and diffusion of individual molecules within a single cell--will be used to describe the precise spatial distribution and temporal dynamics of specific proteins within cells, as measured by microscopic studies of fluorescently labeled proteins. This project will provide new ideas, methods, algorithms and software for spatiotemporal modeling of gene expression and protein dynamics in living cells. It will also provide training for two graduate students, a life scientist and a computer scientist, in modern methods of computational cell biology, mathematical modeling and spatial stochastic simulations.The processes by which bacteria grow, divide and differentiate are of great importance to human welfare because we live in intimate relationships with many types of bacteria. Beneficial bacteria colonize our digestive tract, fix nitrogen for our crops, and produce valuable products in our bioreactors. Pathogenic bacteria cause diseases in us and in our crops and domestic animals. To gain control over both beneficial and pathogenic bacteria, we need to understand the molecular mechanisms governing bacterial reproduction and differentiation. Mathematical models are useful tools for exploring hypotheses about these mechanisms because they integrate a wealth of experimental evidence into a realistic and accurate computer representation of molecular interactions. Computer simulations then serve to test the hypotheses against known experimental facts in a comprehensive fashion and to predict the outcome of novel experimental studies. The cell division cycle of Caulobacter is a favorable case for testing the utility of mathematical modeling in molecular cell biology. In addition, because Caulobacter is closely related to both nitrogen-fixing and disease-causing bacteria and because its asymmetric mode of division is analogous to the reproduction and differentiation of human stem cells, the mathematical methods and biological results expected from this project may ultimately lead to practical developments in agriculture and medicine.