| The transition from rolling to firm adhesion is a key element of neutrophil activation and essential to the inflammatory response. Although selectins and beta2-integrins, the molecular mediators of rolling and firm adhesion, respectively, are well-studied, the precise mechanism by which a neutrophil achieves arrest remains unclear. This dissertation uses applied mathematics and computer simulation to model the phenomena of activation and arrest. Informed by results from detailed simulation, we first develop a semi-analytic model of steady-state leukocyte rolling. This simpler model, when submitted to dimensional analysis, permits a full investigation of the parameterization of rolling behavior and the transition from rolling to firm adhesion. Next, we simulate neutrophil activation by modifying the Adhesive Dynamics algorithm. We employ two different methods, both of which link selectin engagement to integrin activity. First, we include a deterministic, global integrin activation module, based on a Hill function model of the MAPK cascade. Second, using a kinetic Monte Carlo method, we develop a fully-stochastic model of integrin activation which treats the activation of each molecule individually as a function of free energy states. For both deterministic and stochastic activation models, we evaluate a leading activation hypothesis, approximate the observed in vivo behavior of neutrophils, and investigate the roles of various model parameters. |
