A Quantitative Investigation of Chemorepulsion in Eukaryotic Systems

Chemorepulsion is the process by which an organism or a cell moves away from a chemical source or in the direction of decreasing concentration of a chemical stimulus. This phenomenon has been observed in a wide variety of systems ranging from the bacterium Escherichia coli to eukaryotic systems such as human white blood cells. The chemical sources or stimuli are known as chemorepellents. While a few experimental studies have been performed on chemorepulsion, no mathematical models of this process exist. In this thesis, we have analysed the first sub-process of chemorepulsionGradient Sensing. Gradient sensing is the mechanism by which information about the external chemical concentration field is communicated to the cell compass which consequently directs the motility machinery of the cell. Gradient sensing is an important aspect of chemorepulsion as it is the first step in determining the direction of eukaryotic cell migration. We have created a mathematical modelling framework that quantitatively describes gradient sensing in Dictyostelium discoideuman experimentally well characterized eukaryotic system and a recognized model system for studies of cell migration. The underlying biochemical pathways of gradient sensing in D. discoideum are described by the biochemical network created by Keizer-Gunnink et al. (2007). We have systematically analysed the effects of different pathways in the Keizer-Gunnink et al. (2007) network in our modelling framework. First, we have extensively analyzed the adaptive response of the cell to various inputs. Next, the roles of the key phosphatidylinositol lipid enzymes and feedback effects in the Keizer-Gunnink et al. (2007) network have been investigated. We have also carefully investigated the receptor regulation of these enzymes in the network. Overall the construction of the modelling framework has enabled us to carefully analyse the individual mechanisms, their interactions and their contributions towards gradient sensing in D. discoideum. The framework has generated testable predictions regarding the role of key components and feedback loops regulating gradient sensing. We have thus taken the first steps towards quantitatively investigating mechanisms underlying chemorepulsive migration in eukaryotic systems.