| Project/Area Number |
17390357
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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 |
Digestive surgery
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| Research Institution | Hokkaido University |
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Principal Investigator |
OZAKI Michitaka Hokkaido University, Graduate School of Medicine, Professor (80256510)
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| Co-Investigator(Kenkyū-buntansha) |
TODO Satoru Hokkaido University, Graduate School of Medicine, Professor (60136463)
OHKOHCHI Nobuhiro Tsukuba University, Graduate School of Medicine, Professor (40213673)
SUEMATSU Makoto Keio University, Graduate School of Medicine, Professor (00206385)
OGAWA Wataru Kobe University, University hospital, Associate Professor (40294219)
松下 通明 北海道大学, 医学部, 教授 (20250425)
古川 博之 北海道大学, 大学院・医学研究科, 特任教授 (70292026)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥16,750,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2007: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2006: ¥5,300,000 (Direct Cost: ¥5,300,000)
Fiscal Year 2005: ¥5,600,000 (Direct Cost: ¥5,600,000)
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| Keywords | liver regeneration / signal transduction / cell proliferation / cell growth / apoptosis / 分子標的治療 / 脂肪肝 / 加齢 / 肝細胞内シグナル |
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| Research Abstract |
Liver regeneration is composed of a series of complicated processes. The present study was designed to investigate the roles of Jak/STAT3 and PDK1/akt-associated pathways in liver regeneration following partial hepatectomy (PH) using liver-specific STAT3-knockout (L-S3KO), Pdk1-knockout (L-Pdk1KO) and Pdk1/STAT3 double KO (L-DKO) mice.
1) Proliferation of hepatocytes following PH was markedly suppressed in LS3-KO mice with reduced cyclinD1 transcript. However, liver mass recovered sufficiently following PH in LS3-KO mice almost equal to that of control mice. Cell size following hepatectomy was significantly larger in LS3-KO mice than in control mice. Hepatectomy induced immediate but transient phosphorylation of Akt, p70S6K, mTOR and GSK-3b in LS3-KO mice much more than in control mice. Additionally, adenoviral transfection of dominant negative mutant of Akt to control and LS3-KO mice led to insufficient liver regeneration following hepatectomy.
2) 70% PH was lethal in L-Pdk1KO mice with
… More
no liver regeneration. Liver regeneration was severely impaired equally in L-Pdk1KO and L-DKO mice even after non-lethal 30% PH. Measurement of cell size revealed that cell growth following hepatectomy did not occur at all in L-Pdk1KO mice, though post-PH mitotic response occurred to the same degree to the control liver. In L-Pdk1KO mice, post-PH phosphorylation of Akt, mTOR, p70^<56K> and S6 were also reduced.
Re-activation of Akt by introducing 'pif-pocket' mutant of PDK1 in L-Pdk1KO mice lead normal liver regeneration and cell growth in the post-PH liver without affecting cell proliferation. Activation of Pl3-K in the liver of L-Pdk1KO mice increased mitotic cells via STAT3 activation, but did not improve impaired liver regeneration in L-Pdk1KO mice at all. Taken together, these facts indicate that Pl3-K and PDK1/Akt contribute to liver regeneration by regulating cell proliferation and size, respectively. PDK1/Akt-mediated responsive cell growth is essential in normal liver regeneration following PH especially when cell proliferation is impaired. Less
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