| Project/Area Number |
16590289
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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 |
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Principal Investigator |
MASUDA Tomoyuki Iwate Med. Univ., School of Med., Dept. of Pathol., Prof., 医学部, 教授 (10199698)
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| Co-Investigator(Kenkyū-buntansha) |
MAESAWA Chihaya Iwate Med. Univ., School of Med., Dept. of Pathol., Associate Prof., 医学部, 助教授 (10326647)
OIKAWA Hiroki Iwate Med. Univ., School of Med., Dept. of Pathol., Lecturer, 医学部, 講師 (50285582)
ABO Akiko Iwate Med. Univ., School of Med., Dept. of Pathol., Research Associate, 医学部, 助手 (80326686)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2006: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | hepatocyte / stem cell / SP cell / Cellular senescence / cellular differentiation / reconstruction / miRNA / chronic liver injury / 満性肝疾患 / cell sorter / エストロゲン |
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| Research Abstract |
Background and Aim : 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 critical telomere shortening in hepatocytes, we have been focusing on estrogen-dependent transactivation of the human telomerase reverse transcriptase (hTERT) gene as a form of telomerase therapy in chronic liver disease.
Methods : We examined the expression of hTERTmRNA and its protein, and telomerase activity (TA) in 3 human normal hepatic cell lines (He-cells, h-Nheps and WRL-68) before and after treatment with 17β-estradiol (E_2). The effects of exogenous E_2 administration were examined in a CCl_4-induced model of liver fibrosis in rats.
Results : The expression of hTERT mRNA and its protein was up-regulated by E_2-treatment. Telomere length decreased in He-cells and h-Nheps with accumulated passages, whereas that with long-term E_2 exposure was greater than that without E_2. The incidence of β-galactosidase-positive cells, indicating a state of senescence, decreased significantly in E_2-treated cells in comparison with non-treated cells (P<0.05). TA in both male and female rats with CCl_4-induced liver fibrosis was significantly higher with E_2 administration than without (P<0.05). Long-term E_2 administration was able to markedly rescue the hepatic telomere from extensive shortening in both male and female rats.
Conclusion : These results suggest that estradiol acts as a positive modulator of the hTERT gene in the liver. Estrogen-dependent transactivation of the hTERT gene is a new strategy for slowing the progression of chronic liver disease.
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