The overall objective of the proposed research is to identify the mechanisms which limit endothelial cell activation. Since inappropriate or prolonged activation of endothelium is postulated to be involved in atherosclerosis, chronic organ failure and transplant rejection, understanding the mechanisms which limit activation may lead to treatments that improve the outcomes in the disease states mentioned above. Preliminary data indicates that one stimulus that can lead to prolonged activation of endothelial cells is complement activation. The research will determine if limitation of endothelial cell activation is due to receptor down-regulation, intracellular events such as up- regulation of IkappaB or inhibitory genes or to secreted cytokines acting in an autocrine manner. These mechanisms will then be examined in vivo using a porcine model.
