Hepatic ischemic/reperfusion (I/R) injury is characterized by the generation of superoxide anions and other superoxide anion-derived reactive oxygen species (ROS), such as, hydrogen peroxide and hydroxyl radicals. To combat these ROS, free radical scavengers, such as superoxide dismutase (SOD) and catalase play crucial roles in the attenuation of hepatic I/R injury. The general goals of this proposal are to evaluate the therapeutic efficacy of extracellular superoxide dismutase (EC-SOD) and/or catalase gene delivery employing non-viral approaches in a mouse model of hepatic I/R injury, and to develop an ex vivo gene delivery approach for small graft liver transplantation.
Specific Aims : 1. To deliver the EC-SOD and/or catalase gene with polycationic liposomes in order to prevent subsequent liver damage caused by I/R in mice; 2. To develop an ex vivo technique to deliver the EC-SOD and/or catalase gene to small size liver grafts with polycationic liposomes. Methods: In vivo gene delivery efficiency will be evaluated by determining the expression of EC-SOD and catalase in the liver at the mRNA and protein levels. The protection offered by the gene delivery system will be determined by liver biochemistry and histology. The improvement of graft function will be assessed by animal survival, extent of liver injury, and hepatocyte proliferation. The antioxidative effects of both enzymes will be evaluated by lipid peroxidation in the liver tissue. Health Relatedness: The successful completion of the proposed studies will demonstrate that the delivery of these two anti-oxidative enzyme genes is an effective prophylactic strategy for the improvement of graft function, and that the development of a novel gene delivery approach will improve graft quality and survival. ? ? ?
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