This Bioengineering Research Partnership proposal combines expertise from the Bioengineering Department at Rice University and the Section of Leukocyte Biology from Baylor College of Medicine to examine the detailed sequential processes involved in movement of leukocytes from flowing blood to migration in tissues. A systems approach is presented, with the goal of identifying the crucial molecular mechanisms involved at each step and then integration of the steps as would occur in vivo. Both in vitro and in vivo (principally mice) models will be employed - the former to test specific molecular hypotheses and the latter to ensure that mechanisms identified in vitro are of importance in the actual in vivo setting.
Three specific aims are proposed Specific Aim 1 The study of the effects of fluid shear and the interactions of leukocytes and endothelial cells on adherent leukocytes.
This aim will use cone-plate viscometry and parallel plate flow systems to investigate the influence of shear on secretory functions and phenotypic changes in adherent neutrophils Specific Aim 2. The study of the interactions of leukocytes and endothelial cells under shear conditions and the effects on vascular permeability.
This aim will use both in vitro and in vivo experimental models to investigate the sites of neutrophil adhesion and transmigration, and changes in endothelial and vascular permeability Specific Aim 3. The study of the mechanisms of leukocyte migration through extracellular matrix, and the phenotypic changes induced by the processes required for transendothelial migration.
This aim will utilize a synthetic mimetic of extracellular matrix to investigate the contributions of proteolysis, adhesion and haptotaxis in vitro, and intravital microscopy to investigate migration through extracellular matrix in vivo. Basic bioengineering expertise is crucial for the success of each Specific Aim and for the integration of aims - involving aspects of biomechanics, transport phenomena, complex biological systems, cellular engineering and biomaterials. We believe the results of these interdisciplinary studies, combining quantitative bioengineering models, novel biomaterials, basic leukocyte biology and fundamental vascular biology will lead to significant advances in our understanding of leukocyte trafficking, with important implications in both normal physiology and various pathological states.
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