(645a) Integrated Models of Leukocyte Signaling and Adhesion

Cell adhesion receptors secure the adhesion of the cell as well as generate biochemical signals that lead to cell activation; this activation can in turn alter receptor states, further triggering changes in adhesion. We explore this interplay between adhesion and signaling using computational simulations with Adhesive Dynamics, and address the question of how signals might accumulate in a leukocyte during rolling, leading to the onset of firm adhesion. We have simulated the activity of a MAP-kinase pathway, activated by selectin occupancy. As the cell rolls, MAP-kinase is activated, in turn stimulating integrins to be switched to active states. Once sufficiently many are activated, the integrins can stop the cell. We have developed two forms of this simulation - one in which the signaling is deterministic and temporal, but not spatial; and another where the stimulation is spatial and stochastic. In both cases, we define how key system parameters can control cell stopping. We can easily match time-scales for cell docking that are observed in the microvasculature, and show how the regulation of key intracellular enzymes can regulate firm binding. Ongoing work addresses the role of G-protein coupled receptor activation on leukocyte firm adhesion, and how chemokine receptors might induce lymphocytes to dock during lymphocyte homing.