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. 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, 2, 3 and 4 have a common focus and employ complementary approaches to understand what governs integrin-mediated neutrophil attachment and migration. A particular emphasis is to relate behaviors observed in vitro (Projects 1, 2 and 3), where we can obtain precise understanding of regulatory mechanisms of adhesion, to clinically relevant events in vivo (Projects 2 and 4). Project 1 uses quantitative models and molecular approaches to understand signaling events connecting chemokine stimulus to integrin activation and cell immobilization in flow, as well as experiments on force generation during neutrophil crawling (with Projects 2 and 3). Project 2 uses molecular approaches to learn how integrin affinity is regulated in distinct regions of migrating cells both in vitro and in vivo. Project 3 uses single cell experiments to reveal how molecular diffusion and surface topography affect adhesion and the initiation of cell crawling, and to characterize the dynamics of signaling pathways leading to changes in integrin affinity and avidity. Project 4 focuses on the mechanisms underlying leukocyte-endothelial interaction in vivo, with emphasis on the functional consequences of heterogeneities in adhesion molecule expression, and signaling events in endothelial cells (EC) initiated by leukocyte ligation. Project 5 uses both computational and experimental approaches to study mechanisms related to cell capture, particularly with respect to ways that multiparticle hydrodynamics and shear stress may affect cell capture and cell activation (with Projects 1 and 4). In addition to computational studies to determine consequences of abnormal cell geometry on cell capture. Project 5, with Project 3, is exploring mechanotransduction mechanisms affecting L-selectin shedding and neutrophil response to agonists via G-protein coupled receptors. Peripheral vascular dysfunction is integral to pathology associated with the most serious diseases in western society, including heart disease, stroke, and cancer metastasis, as well as disorders involving inflammation and immunity. The underlying mechanisms for these involve mechanical forces, molecular interactions and cellular properties acting synergistically in ways that are uniquely addressed by this program.
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