Cell migration is central to many biological and pathological processes, including embryogenesis, tissue repair and regeneration as well as cancer and the inflammatory response. Inflammatory recruitment of leukocytes is critical in initiation and progression of a wide range of cardiovascular diseases including vasculitis and atherosclerosis. Integrin LFA-1 is a critical component in the effective trafficking of leukocytes. In various pathologic conditions, sustained or dysregulated integrin activation causes aberrant leukocyte infiltration and tissue damage. Therefore, studies of the functions of the integrins and the regulation of cell adhesiveness and migration through them are of great importance in enhancing our ability to develop better- targeted and more effective anti-inflammatory therapies. Although a great deal of information has been learned about the sequential action of chemoattractants and adhesion molecules that mediate the early steps in leukocyte extravasation, including tethering, rolling and firm adhesion, little is known about dynamic and spatial regulation of integrin activation during leukocyte polarization and migration. The central hypothesis of the proposed study is that a small subpopulation of cell surface LFA-1 become activated and localize to the leading edge of polarized cells to mediate migration, which are then switched to low affinity at the uropod allowing efficient tail retraction. Using dynamic fluorescence resonance energy transfer (FRET) assay, we will visualize temporo-spatial LFA-1 activation during lymphocyte chemotaxis. The effects of selective inhibition of the high affinity LFA-1 using a newly developed monoclonal antibody and its advantages over conventional non-selective anti-adhesion agents will be tested. Integrins transduce bidirectional signals across the plasma membrane through conformational changes (affinity regulation) and clustering in the cell membrane (avidity regulation) that regulate extracellular adhesiveness and intracellular signaling. The effects of selective inhibition of the two distinctive mechanisms on lymphocyte migration will be investigated with small molecule antagonists. Finally, we will determine the distinct signaling networks associated with LFA-1 activation at the leading edge, and de-activation at the trailing edge during dynamic lymphocyte migration. This study will enhance our understanding of pathogenic factors that are relevant to a wide range of inflammatory diseases and may reveal new approaches for therapeutic intervention. ? ? ?
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