2005 Fiscal Year Final Research Report Summary
The molecular mechanism of the impaired regeneration of biliary epithelial cells in bile duct vanishing syndrome.
| Project/Area Number |
15590297
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 |
SASAKI Motoko Kanazawa University, Graduate School of medicine, Associate Professor, 医学系研究科, 助教授 (70225895)
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| Co-Investigator(Kenkyū-buntansha) |
SATO Yasunori Kanazawa University, Graduate School of medicine, Instructor, 医学系研究科, 助手 (30324073)
NAKANUMA Yasuni Kanazawa University, Graduate School of medicine, Professor, 医学系研究科, 教授 (10115256)
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| Project Period (FY) |
2003 – 2005
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| Keywords | bile duct vanishing syndrome / primary biliary cirrhosis / trefoil factor family (TFF) / intrahepatic bile duct / biliary epithelial cell / immunohistochemistry / cellular senescence |
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| Research Abstract |
The impaired regeneration of biliary mucosa may be related to the pathogenesis of bile duct loss in vanishing bile duct syndrome. We examined immunohistochemically the expression of trefoil factor family (TFF)-1,2,3, a putative receptor for TFF2:DMBT1, hepatocytes growth factor (HGF) related factors (HGFA,HAI-1,cMET) and the involvement of cellular senescence in intrahepatic bile ducts in the livers taken form the patients with vanishing bile duct syndrome (n=45) including primary biliary cirrhosis (PBC) and control livers (n=65). In intrahepatic biliary system, the site-characteristic distribution of TFF1-3 was seen and TFF1, 3 and TFF2 play a role in the mucosal repair in large and small intrahepatic bile ducts, respectively. The expression of TFF2, DMBT1 and HAI-1 was increased in the damaged bile ducts in PBC. Furthermore, the biliary epithelial cells showed the features for cellular senescence such as the increased expression of p16^<INK4a> and p21^<WAF1/Cip> in the damaged bile ducts in PBC and in the livers of chronic allograft rejection. The decreased expression of bmi1, a represser of p16^<INK4a> was involved in the cellular senescence of biliary epithelial cells. The mRNA expression of these factors was in accord with the protein expression detected by immunohistochemistry. The oxidative stress and several cytokines such as TNF-alpha increased the expression of TFFs and HAI-1 in cultured mouse biliary epithelial cells. In addition, oxidative stress decreased the expression of bmi1, increased the expression of p16^<INK4a> and p21^<WAF1/Cip> and induced cellular senescence in cultured mouse biliary epithelial cells. Taken together, TFF-1,2,3 and HGF related factors were involved in the mucosal repair system in the intrahepatic biliary system as well as in the gastrointestinal tracts. The cellular senescence of biliary epithelial cells may be a main cause for the impaired regeneration and following bile duct loss in vanishing bile duct syndrome.
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