NSF Award Abstract - #0083500

AWSFL008-DS3

BIOCOMPLEXITY: Mathematical and Biological Modeling of Cell Polarization

Abstract

This research project integrates experimental research on the biochemical aspects governing chemotaxis in Dictyostelium discoideum with theoretical developments from control engineering and dynamical systems theory. Chemotaxis - the ability to sense the direction of external chemical sources and respond by polarizing and migrating toward chemoattractants or away from chemorepellants - is crucial for proper functioning of single cell organisms, such as bacteria and amoebae, as well as multi-cellular systems. In fact, chemotaxis occurs to some extent in almost every cell type at some time during its development. It is a major component of the inflammatory, and wound-healing responses, the mammalian reproductive systems (spermatozoa), the development of the nervous system as well as tumor metastasis. Despite of recent advances in the understanding of the biochemistry regulating chemotaxis in eukaryotic cells -specially of the slime mold D. discoideum, knowledge of the signaling network is far from complete. Nevertheless, this signaling network serves as a particularly timely candidate for mathematical and computational modeling, as well as an ideal model organism for discovering how cells sense and respond to directional external stimuli. The introduction of control engineering and dynamical systems theory into this research is particularly appropriate as these fields focus on nonlinear phenomenon, particularly those involving feedback systems and thus provide a natural counterpoint to biochemical research. Specifically, in this research we propose to 1) localize the signaling proteins in living cells undergoing chemotaxis; 2) account for the source and nature of signal amplification; 3) explore the mobility of signaling proteins during chemotaxis; 4) determine the roles that conflicting chemoattractants have on cell polarity; and 5) ascertain the robustness properties of this cell signaling mechanism. Our goal is to develop high-fidelity models of the regulatory network controlling eukaryotic chemotaxis.

Eukaryotic chemotaxis is a fascinating biological phenomenon. A thorough understanding will represent a huge step forward in our knowledge of one of the basic properties of life, i.e. purposeful movement, and enable a logical approach to the treatment of many devastating human diseases that result when this process fails. Moreover, the similarity of the chemotactic responses in mammalian cells to those of D. discoideum ensures that the proposed research will have far reaching impact beyond this organism.