Molecular and cellular biological analyzes of morphogenesis modulated by HGF

HGF 调节形态发生的分子和细胞生物学分析

基本信息

批准号：
08408027
负责人：
NAKAMURA Toshikazu
金额：
$ 23.42万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

项目摘要

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 … More 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

1. 连续喂食含乙醇饮食37天的大鼠，肝脂质和肝细胞内脂滴积累显着增加，表明在乙醇治疗的最后7天给予肝细胞生长因子（HGF）显着发病。肝脂质水平低于HGF治疗前的水平。2.在通过二甲基亚硝胺给药产生的致死性肝硬化大鼠模型中，重复转染将人类 HGF 基因导入骨骼肌可诱导人类以及内源性大鼠 HGF 血浆水平升高，并且用 HGF 基因转导 c-Met/HGR 受体的酪氨酸磷酸化也可抑制纤维形成和肝细胞凋亡，并完全消除纤维化。 3. 慢性肾病自发小鼠模型（ICGN品系），在自发性小鼠模型中，肾小球逐渐出现硬化损伤、肾小管萎缩和肾功能障碍，直到 17 周龄时，连续 4 周（从第 14 周到第 17 周）施用 HGF 可以阻止肾功能障碍和纤维化的进展。用于慢性肾病（ICGN菌株）。4.在培养的心肌细胞和心脏内皮细胞中以及在再灌注心肌的活边界区中产生HGF。与盐水治疗相比，给予HGF和HGF基因可显着减少大鼠再灌注心肌损伤中的梗死面积和凋亡性心肌细胞死亡。5．微型泵减轻了急性脑缺血模型中大脑皮层的延迟性神经细胞死亡。7。 HGF的四环片段，HGF/NK4在体内和体外抑制肿瘤的侵袭，并且HGF/NK4还竞争性抑制HGF与GB-d1人胆囊癌细胞上的Met/HGF受体的结合，增加植入的 GE-d1 凋亡细胞死亡并抑制体内肿瘤生长。除了对 HGF 的拮抗活性外，HGF/NK4 还抑制由 HGF 诱导的血管生成。 FGF、VEGF 和 HGF 在体外和体内的作用，以及肿瘤（例如 Lewis 肺癌细胞）的生长大小和血管生成的减少，表明 HGF 对肿瘤生长和侵袭的双潜能作用较小。