The theme of this program project is the inter-relation of mechanics, chemistry and hydrodynamics as underlying mechanisms in normal and pathological peripheral vascular function, particularly the inflammatory response. Peripheral vascular dysfunction is integral to the pathology associated with the most serious diseases in Western society, including heart disease, stroke, and cancer metastasis, and also play a fundamental role in other disorders involving inflammation and immune response. Five projects are engaged in synergistic studies designed to reveal fundamental mechanisms underlying both normal and pathological phenomena in the peripheral vasculature with a central focus on neutrophil-endothelial interactions. Projects 1 and 3 have a common focus and employ complementary approaches to understand fundamental chemical and physical factors that govern interactions between neutrophils and endothelium, particularly the transition from selectin-mediated rolling interactions to integrin-mediated neutrophil attachment and migration. A particular emphasis is to relate behaviors observed in vitro, from which we can obtain precise understanding of regulatory mechanisms of adhesion, to clinically relevant events in vivo (with Project 4). Project 2 focuses on mechanisms regulating adhesion molecule expression and activation in neutrophils, with a focus on the role that anion transport plays in that regulation and the identification of potential targets for therapeutic intervention. In collaboration with all other projects, the consequences of altered adhesion molecule expression on neutrophil adhesion will be delineated. Project 4 focuses on the mechanisms underlying leukocyte-endothelial interaction in vivo, with emphasis on the functional consequences of heterogeneities in adhesion molecule expression, the relative roles of adhesion molecule expression and hydrodynamics in leukocyte recruitment (with Project 5) and the role of calcium signaling in neutrophil-endothelial communication. Project 5, uses computational tools (with Project 1) and artificial vascular constructs in vitro to identify the importance of hydrodynamics, cell-cell interactions, and cell deformability (with Project 3) in determining dominant sites of leukocyte-endothelial interactions. A major goal (with Project 4) is to develop realistic computational models to evaluate the critical roles that vascular geometry and heterogeneity in adhesion molecule expression have on leukocyte capture.
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