This grant, first funded in 1981, is a continuing exploration of the hypothesis that (a) endothelial cell (EC) surface proteins regulate EC interactions with leukocytes;and (b) that inflammatory cytokines like tumor necrosis factor (TNF) exert their effects by altering EC surface protein expression. In the next funding cycle, the specific aims are: (1) to determine the basis of differences in the TNF responsiveness of arterial vs. venous EC, focusing on E-selectin, a TNF induced protein discovered by this grant that mediates leukocyte adhesion;(2) to elucidate the molecular basis of the up regulation of TNF receptor (TNFR) 2 expression on EC caused by changes in oxygen levels (as observed in vivo following ischemia/reperfusion injury);(3) to discover how caveolae and/or lipid rafts can modulate TNF signaling responses of EC, especially the activation of ERK-1,2 and of Akt through TNFR1 as well as ligand-induced TNFR1 internalization and intracellular trafficking;and (4) to discover the mechanisms by which TNF increases protein transit across EC monolayers (""""""""vascular leak""""""""), focusing upon changes in tight junctions and the proteins that form them. These experiments will use a variety of human EC culture systems and analyze these by molecular, immunochemical, morphological and functional approaches. We will also use human mouse chimeric animals to study TNF responses of human EC in vivo. Successful completion of these aims will advance our understanding of TNF responses and may provide the basis for advancing therapeutic approaches to control inflammation.
Tumor necrosis factor (TNF) is a protein secreted by white blood cells that causes inflammation and works, in large part, by acting on the endothelial cells that line blood vessels to change their cell surface from one that repels circulating white blood cells to one that attracts them. This grant will study mechanisms of how TNF causes endothelial cells to change their cell surface. An understanding of these mechanisms can be used to develop new therapies to treat inflammatory diseases such as rheumatoid arthritis or inflammatory bowel disease, or diseases with inflammatory components such as atherosclerosis, heart failure or stroke.
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