| Project/Area Number |
14570156
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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 | Iwate Medical University School of Medicine |
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Principal Investigator |
MASUDA Tomoyuki Iwate Med. Univ. School of Med., Dept. of Phatol., Professor, 医学部, 教授 (10199698)
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| Co-Investigator(Kenkyū-buntansha) |
OIKAWA Hiroki Iwate Med. Univ. School of Med., Dept. of Pathol, Assistant, 医学部, 助手 (50285582)
MAESAWA Chihaya Iwate Med. Univ. School of Med., Dept. of Pathol., Lecturer, 医学部, 講師 (10326647)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2002: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | stem cell / hTERT / TRE assay / replicative senescence / estradiol / biomolecular ineraction / telomere / telomerase / 肝臓 / 肝不全 |
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| Research Abstract |
Significant telomere shortening of hepatocytes is associated with replicative senescence and a non-dividing state in chronic liver disease, resulting in end-stage liver failure and/or development of hepatocellular carcinoma. To prevent hepatocytes from critical telomere shortening, we are focusing on an estrogen-dependent transactivation of human telomerase reverse transcriptase (hTERT) gene as a telomerase therapy in chronic liver disease. We examined hTERTmRNA and protein expressions, and telomerase activity (TA) in 3 human normal hepatic cell lines (Hc-cells, h-Nheps and WRL-68) before and after treatment with 17β-estradiol (E2). The hTERT mRNA and protein expressions were up-regulated in Hc-cells and h-Nheps by E_2-treatment, while overexpression of hTERT gene was observed in WRL-68 even before the treatment. Telomere length decreased with accumulated passages in Hc-cells and h-Nheps, whereas that with long-term E_2 exposure was longer than that without E_2. Incidence of β-galactosidase positive cells, indicating senescence state, significantly decreased in E_2-treated cells in comparison with non-treated cells (P<.05). Effects of exogenous E_2 administration on TA and telomere length were examined in CCl4-induced liver fibrosis model of rats. TA of both male and female rats of CCl4-induced liver fibrosis with E_2 administration significantly higher than those without E_2 administration (P<.05). Gender-related difference in TA was not observed. Long-term E_2 administration could drastically rescue the hepatic telomere from extensive shortening in both male and female rats. These results suggest that estradiol acts as a positive-modulator of hTERT gene in the liver and may prolong the lifespan of hepatocytes by the prevention of extensive telomere shortening. The estrogen-dependent transactivation of the hTERT gene is a new strategy for slowing the progression of chronic liver disease.
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