| Co-Investigator(Kenkyū-buntansha) |
FUNAKOSHI Hiroshi Osaka University, Dept of Oncology, Assisitant Prof., 医学部, 助手 (40273685)
KOSHIMIZU Uichi Osaka University, Dept of Oncology, Assistant Prof., 医学部, 助手 (50281126)
MIYAMOTO Kazumasa Osaka University, Dept of Oncology, Assistant Prof., 医学部, 助手 (60273679)
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| Research Abstract |
1. Rats fed ethanol-containing diets for 37 days showed remarkable increase in hepatic lipids and lipid droplet accumulation in the hepatocytes, indicating the onset of alcholic fatty liver. Administration of hepatocyte growth factor (HGF) for the last seven days of ethanol treatment markedly decreased hepatic lipids to the level lower than that seen before HGF treatment.
2. In a rat model of lethal liver cirrhosis produced by dimethylnitrosamine administrations, repeated transfections of the human HGF gene into skeletal muscles induced ahigh plasmalevel of human as well as endogeneous rat HGF, and tyrosine phosphorylation of the c-Met/HGR receptor. Transduction with the HGF gene also inhibited fibrogenesis and hepatocyte appoptosis, and produced the complete resolution of fibrosis in the cirrhotic liver, thereby improving the survival rate of rats with this severe illness.
3. The mice, a spontaneous mouse model for chronic renal disease (ICGN strain), progressively developed glomerular
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sclerotic injury, tubular atrophy and renal disfunction until they were 17 wk of age. Administration of HGF for 4-wk-periods(from weeks 14-17) prevented the progression of renal dysfunction and fibrosis in a spontaneous mouse model for chronic renal disease (ICGN strain).
4. HGF was produced in cardiomyocytes and cardiac endothelial cells in culture, and in viable border zone of reperfused myocardiac infarction. Administration of HGF and HGF gene markedly decreased infarct area and apoptotic cradiac cell death in rat postreperfusion myocardial injury, compared with saline treatment.
5. HGF prevented cerebral corteical neuronal cell induced by glutamate.
6. Continuous intra-ventricular administration of HGF by mini-pump attenuated delayed neuronal cell death of cerebral cortex in acute brain ischemic model.
7. We have previously demonstrated a four-kringle-containing fragment of HGF, HGF/NK4 inhibits invasion of tumors in vivo, as well as in vitro, and HGF/NK4 also competitively inhibited the binding of HGF to Met/HGF receptor on GB-d1 human gallbladder carcinoma cells, increased apoptosis of implanted GE-d1 apoptotic cell death and inhibited this tumor growth in vivo. In addition to the antagonistic activity against HGF, HGF/NK4 inhibited angiogenesis induced by FGF, VEGF and HGF in vitro and in vivo, and decreased growth size and angiogenesis of tumors, such as Luwis lung cancer cells, suggesting bipotential role of HGF for tumor grwoth and invasion. Less
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