Vascular endothelium, interacting with circulating blood cells and humoral mediators plays a central role in the pathogenesis of acute and chronic inflammation, hemostasis and thrombosis, immunological reactions, vascular injury and repair, and various vascular disease. Since its inception, 20 years ago, this Program Project has combined cell and molecular biological, biochemical, morphological, immunological, and experimental pathological approaches to gain new insights into the active role of the endothelium in these important disease processes. In this competitive renewal application, we propose to define intracellular and intercellular signaling pathways that integrate and regulate various endothelial-dependent mechanisms in inflammation and response-to-injury reactions using both in vitro and in vivo experimental strategies. The first project will study the mechanisms and consequence of signaling via E-selectin during leukocyte-endothelial interactions in inflammation. This project will focus on the dynamic regulation of the endothelial lateral junction complex during inflammatory leukocyte recruitment. This project will characterize the role of specific protease- activated receptors in thrombin-mediated endothelial responses. This project will focus on endothelial-induced signals that enhance effector and regulatory responses for T lymphocytes. This project will focus on endothelial-induced signals that mechanisms in the transcriptional regulation of cytokine-activated endothelial genes. This project will identify endothelial-derived factors that act to delay the programmed cell death of emigrated neutrophils at sites of inflammation. Cell Biology Support core will provide well characterized vascular cell cultures (human, mouse); hybridoma and embryonic stem cell maintenance; isolation of human blood ells; computerized biological imaging and intravital fluorescence microscopy. Morphology Support core will assist in immunohistochemistry, in situ hybridization, and histopathologic examination of tissues.
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