(verbatim from the proposal): Leukocytes interacting with the endothelium at sites of acute inflammation pass through a multistep cascade of events initiated by leukocyte margination to the vessel wall and proceeding to transmigration into the tissue. While members of the selectin family mediate the tethering and rolling of PMNs on the endothelium, cell arrest is dependent on members of the beta2-integrin family. This process is critical for initiation of the host immune response to bacterial and fungal pathogens, and is a common target for therapeutic intervention in inflammation. Central to the transition from cell tethering to stable adhesion and transmigration is the activation of leukocyte integrins to bind to intercellular adhesion molecule-1 (ICAM-1) upregulated on inflamed endothelium. The formation of integrin bonds in sufficient number provides the cell adhesion strength that balances the drag forces of flowing blood. This multistep process of emigration also applies to neutrophil-neutrophil aggregation. We have established that homotypic aggregation also requires L-selectin tethering and beta2-integrin binding. Current published data suggest that selectin receptors can also function as signal transduction molecules in facilitating leukocyte activation. In this application we will test the hypothesis that tethering and signaling through selectins serves to increase the efficiency of margination, firm adhesion, and transmigration of neutrophils.
Two specific aims are proposed. 1) To determine the biophysical mechanisms underlying the transition from selectin tethering to integrin-dependent firm adhesion under defined shear. 2) To examine how tethering through L-selectin signals PMN activation and integrin-dependent adhesion. Our experimental strategy is to study neutrophils isolated from human blood and maintained in a pristine state. Only in this manner can we attempt to apply viscometry and flow cytometric techniques to measure the rapid molecular recognition and signaling events under defined hydrodynamic shear fields with millisecond resolution. Neutrophil-neutrophil, and neutrophil-endothelial adhesion will be measured in native cells and stable cell lines transfected to express specific leukocyte and vascular adhesion molecules. The overall objective of these studies is to reveal the dual functions of the selectins in tethering and signaling adhesion functions in neutrophils.
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