Transplantation of the liver is an accepted therapy for children and adults with end-stage liver disease. Current demand for available livers demonstrates that there are two patients registered for every liver that will be transplanted within the given year. A major problem in liver preservation is primary graft non-function that occurs in approximately 10% of the patients. Further, 72% of those livers available for transplantation into acceptable donors are not used because of one or more exclusion criteria. This research group has focused on the cellular mechanisms of storage-reperfusion injury and elucidated the role of reperfusion-induced endothelial cell killing and Kupffer cell activation in storage-related liver graft dysfunction and failure. This work led to development of Carolina Rinse Solution, which improves graft viability by preventing reperfusion-induced endothelial cell killing and Kupffer cell activation. This application will now focus on the molecular events accompanying this injury.
The specific aims are to 1) test the hypothesis that the cyto-protective amino acid, glycine, inhibits an organic anion channel in endothelial cells and a hyperpolarizing chloride channel in Kupffer cells; 2) assess the hypothesis that PGE2 formation by Kupffer cells mediates preconditioning of endothelial cells by endotoxin and ischemia against storage-related cell killing; 3) characterize the cellular and molecular basis for storage-related apoptosis after rat liver transplantation; and 4) apply gene therapy to improve liver preservation for transplantation, specifically by transfecting genes for superoxide dismutase and catalase and the anti-apoptotic gene bcl-2. These molecular issues will be investigated in cultured cell systems and perfused livers using a variety of techniques, many of which were developed by this group using cell biology, pharmacology, biochemistry and molecular biology. Further, the investigators will validate their findings in a clinically relevant model of rat liver transplantation.
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