| Project/Area Number |
12470044
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Human pathology
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| Research Institution | Kanazawa University |
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Principal Investigator |
NAKANUMA Yasuni Kanazawa Univ., Graduate School of Medical Science, Prof., 大学院・医学系研究科, 教授 (10115256)
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| Co-Investigator(Kenkyū-buntansha) |
HARADA Kenichi Kanazawa Univ., Graduate School of Medical Science, Lecture, 大学院・医学系研究科, 講師 (30283112)
SASAKI Motoko Kanazawa Univ., Graduate School of Medical Science, Assitant Prof., 大学院・医学系研究科, 助教授 (70225895)
常山 幸一 金沢大学, 大学院・医学系研究科, 助手 (10293341)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2001: ¥2,900,000 (Direct Cost: ¥2,900,000)
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| Keywords | Human Pathology / Pathology of Liver / Molecular Biology / Congenital Hepatic Fibrosis / Caroli's Disease / Animal Model / PCK Rat / サイトケラチン20 / 上皮成長因子 / 細胞内シグナル伝達 / 細胞増殖 / 肝内胆管 / 体染色体性劣性遺伝 / アポトーシス / cDNAマイクロアレイ / TGF-βファミリー |
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| Research Abstract |
Carolis disease and congenital hepatic fibrosis(CHF) belong to hepatic fibropolycystic disease. In this study, we used a novel polycystic kidney(PCK) rat, which spontaneously develops hepatic cysts, and characterized the hepatobiliary lesions.
1)The cystic changes of the liver of the PCK rats were found to be multiple segmental and saccular dilatations of the intrahepatic biliary tree. These features were very similar to those of Caroli's disease and CHF, demonstrating that the PCK rat could be a promising animal model of Caroli's disease with CHF.
2)In the basement membrane of the dilated intrahepatic bile ducts of PCK rats, the expression of extracellular matrix components such as laminin and type IV collangen were reduced or diminished, and the same phenomena were observed In the liver of patients with CHF and Caroli's disease. Abnormal interactions between bile duct epithelia and surrounding basement membrane may play an important role in the hepatobiliary abnormalities of CHF and Caroli's disease as well as the PCK rats.
3)The expression pattern of fibrogenic factors such as CTGF and TGF-β in the patient liver of CHF and Caroli's disease was different from those of the chronic hepatitis and alcoholic liver disease, suggesting that different mechanism of hepatic fibrosis exists in these disease.
4)The cultured intrahepatic biliary epithelial cells(BECs) of the PCK rats were established. Proliferative activity of the cultured BECs of PCK rats were higher than those of the control rats. cDNA microarray analysis showed overexpression of the genes associated with cell proliferation and apoptosis such as MEK5, TGF-β3 and bFGF. The BECs of PCK rats were shown to be hyperresponsive to EGF, and EGF receptor tyrosine kinase inhibitor significantly inhibited abnormal growth of BECs of the PCK rats.
The data obtained here provide insights into the pathogenesis of CHF and Caroli's disease.
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