| Budget Amount *help |
¥6,800,000 (Direct Cost: ¥6,800,000)
Fiscal Year 1994: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1993: ¥5,100,000 (Direct Cost: ¥5,100,000)
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| Research Abstract |
Protetion of tissues from oxygen toxicity is one of the major prerequisite to aerobic life. Reactive oxygen species rapidly react with various molecules and interfere cellular functions.To minimize oxygen toxicity, these reactive species should be scavenged effectively at the site of generation.Although Cu/Zn-type superoxide dismutase (SOD) has successfully been used to inhibit oxygen toxicity in vitro, intravenously injected SOD rapidly disappears from the circulation with a half-life of 5 min and, hence, it has been practically difficult to use SOD as a therapeutics. To inhibit oxidative stress caused by superoxide and its metabolites, we have developed several types of site-directed SOD derivatives.
1 SOD which circulates with prolonged half-life (T_<1/2>=6-8 hr)
2 Nephrophilic SOD which specifically localizes in proximal tubule cells
3 SODs which bind to galactose and mannose receptors on hepatocytes and Kupffer cells
4 SOD which selectively binds to vascular endothelial cells
Due to such unique properties of these SOD derivatives, the enzymes effectively inhibited cell and tissue injury associated with brain edema, stress-induced gastric mucosal injury, liver transplantation, ischemic damage of liver, kidney and intestines and revealed a marked depressor action in hypertensive rats with genetic and nongenetic etiology. Kinetic experiments using these derivatives indicated that cross-talk between superoxide, nitric oxide and related free radicals plays critical roles in the pathogenesis of these diseases and that these site-directed SOD derivatives have therapeutic potential in oxidative tissue injury.
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