COMPUTATIONAL MODELING AND SIMULATION OF RECEPTOR-MEDIATED LEUKOCYTE ROLLING AD

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Leukocyte homing in past-capillary vessels is critical in inflammatory response of the body during tissue injury, attack by foreign elements, or even in case of atherosclerosis. Through a complex multi-step process, circulating leukocytes are captured from the flowing blood in to the vascular endothelium. Mediated by selectin molecules expressed on the leukocyte membrane and on endothelial, leukocytes perform slow rolling. Subsequently, leukocytes are firmly adhered by integrin molecules, and transmigrate through endothelial fenestration to the sites of inflammation or tissue injury. The selectin-mediated slow rolling of leukocytes is crtical as it allows the cells to `search( for targeted sites. Leukocyte rolling and adhesion occurs under a balance between the hydrodynamic force of the blood flow, and the adhesion force of the receptor/ligand bonds formed between the cell membrane and the endothelium. The proceess is of multiscale in nature -- the macroscopic motion of the blood plasma provides the driving force, whereas the nanoscale adhesion force provide the stability of the cells. In order to understand how under the hydrodynamic dispersive forces, the selectin bonds mediate cell rolling, we plan to develop a multi-scale computational technique to address cell/substrate and cell/cell adhesion under hydrodynamic flowing condition. The computational method will consist of three-dimensional fluid flow solver (navier-Stokes solver) based on immersed boundary method to consider deformation of the cell during its adhesion to endothelium. The macroscopic fluid dynamics will be coupled to the molecular bond formation by stochastic simulation in which formation of selectin bonds will be simulated by Monte Carlo method. The research will elucidate how cellular properties, and biophysical parameters of selectin bonds promote cell adhesion under a stressful hydrodynamic environment.