2007 Fiscal Year Final Research Report Summary
comprehensive study on the mechanisms of liver regeneration toward clinical molecular targeting therapy
| 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)
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| Project Period (FY) |
2005 – 2007
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| Keywords | liver regeneration / signal transduction / cell proliferation / cell growth / apoptosis |
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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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[Journal Article] Identification of de novo STAT3 target gene in liver regeneration.2008
Author(s)
Hui-qi Zhang, Sanae Haga, Moto Fukai, Yuko Oikawa, Hiroshi Inoue, Wataru Ogawa, Arihiko Kano, Atsushi Maruyama, Xin-Yuan Fu, Hiroyuki Furukawa, Satoru Todo, Shin Enosawa, Michitaka Ozaki^*.
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Journal Title
Hepatol Res 38(4)
Pages: 374-84
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Platelets strongly induce hepatocyte proliferation with IGF-1 and HGF in vitro.2008
Author(s)
R Matsuo, N Ohkohchi, S Murata, O Ikeda, Y Nakano, M Watanabe, K Hisakura, A Myronovych, T Kubota, H Narimatsu, M Ozaki.
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Journal Title
Journal of Surgical Research 145
Pages: 279-286
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Identification of de novo STAT3 target gene in liver regeneration.2008
Author(s)
Hui-qi Zhang, Sanae Haga, Moto Fukai, Yuko Oikawa, Hiroshi Inoue, Wataru Ogawa, Arihiko Kano, Atsushi Maruyama, Xin-Yuan Fu, Hiroyuki Furukawa, Satoru Todo, Shin Enosawa, Michitaka Ozaki.
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Journal Title
Hepatol Res 38(4)
Pages: 374-84
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Platelets strongly induce hepatocyte proliferation with IGF-1 and HGF in vitro.2008
Author(s)
R Matsuo, N Ohkohchi, S Murata, 0 Ikeda, Y Nakano, M Watanabe, K Hisakura, A Myronovych, T Kubota, H Narimatsu, M Ozaki.
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Journal Title
J Surgical Res 145
Pages: 279-286
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] AFPmRNA detected in bone marrow by real-time quantitative RT-PCR analysis predicts survival and recurrence after curative hepatectomy for hepatocellular carcinoma.2006
Author(s)
Toshiya Kamiyama, Masato Takahashi, Takahito Nakagawa, Kazuaki Nakanishi, Hirofumi Kamachi, Tomomi Suzuki, Tsuyoshi Shimamura, Masahiko Taniguchi, Michitaka Ozaki, Michiaki Matsushita, Hiroyuki Furukawa, Satoru Todo.
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Journal Title
Ann Surg 244
Pages: 451-463
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] AFPmRNA detected in bone marrow by real-time quantitative RT-PCR analysis predicts survival and recurrence after curative hepatectomy for hepatocellular carcinoma.2006
Author(s)
Toshiya Kamiyama, Masato Takahashi, Takahito Nakagawa, Kazuaki Nakanishi, Hirofumi Kamachi, Tomomi Suzuki, Tsuyoshi Shimamura, Masahiko Taniguchi, Michitaka Ozaki Michiaki Matsushita, Hiroyuki Furukawa, Satoru Todo.
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Journal Title
Ann Surg 244
Pages: 451-463
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Compensatory recovery of liver mass by Akt-mediated cellular hypertrophy in liver-specific STAT3-deficient mice.2005
Author(s)
Sanae Haga, Wataru Ogawa, Hiroshi Inoue, Keita Terui, Tetsuya Ogino, Rumi Igarashi, Kiyoshi Takeda, Shizuo Akira, Hiroyuki Furukawa, Satoru Todo, Shin Enosawa, Michitaka Ozaki.
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Journal Title
J Hepatol 43(5)
Pages: 799-807
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Prolonged survival of donor-specific rat intestinal allograft by administration of bone-marrow-derived immature dendritic cells.2005
Author(s)
Dong Sheng Sun, Hiromi Iwagaki, Michitaka Ozaki, Tetsuya Ogino, Satoshi Kusaka, Yoshimi Fujimoto, Hiroshi Murata, Hiroshi Sadamori, Hiroyoshi Matsukawa, Noriaki Tanaka, Takahito Yagi.
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Journal Title
Transpl Immunol 14
Pages: 17-20
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Compensatory recovery of liver mass by Akt-mediated cellular hypertrophy in liver-specific STAT3-deficient mice.2005
Author(s)
Sanae Haga, Wataru Ogawa, Hiroshi Inoue, Keita Terui, Tetsuya Ogino, Rumi Igarashi, Kiyoshi Takeda, Shizuo Akira, Hiroyuki Furukawa, Satoru Todo, Shin Enosawa, Michitaka Ozaki
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Journal Title
J Hepatol 43(5)
Pages: 799-807
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Prolonged survival of donor-specific rat intestinal allograft by administration of bone-marrow-derived immature dendritic cells.2005
Author(s)
Dong Sheng Sun, Hiromi Iwagaki, Michitaka Ozaki, Tetsuya Ogino, Satoshi Kusaka, Yoshimi Fujimoto, Hiroshi Murata, Hiroshi Sadamori, Hiroyoshi Matsukawa, Noriaki Tanaka, Takahito Yagi
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Journal Title
Transpl Immunol 14
Pages: 17-20
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Analysis of liver renegeration signal and factor of regeneration incompetence-Responsible signal of hepatocyte proliferation-growth-apoptosis after partial hepatectomy and effect of liver, regeneration.2007
Author(s)
Michitaka Ozaki, Sanae Haga, Rumi Igarashi, Tadahiro Osada, Hiroshi Inoue, Wataru Ogawa, Hiroshi Murata, Hiromi Iwagaki, Hiroyuki Furukawa, Satoru Todo
Organizer
14^<th> the Japanese Society for the Research of Hepatic Cells
Place of Presentation
Kagoshima
Year and Date
20070622-23
Description
「研究成果報告書概要(欧文)」より
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[Presentation] 肝再生の分子機構2007
Author(s)
尾崎倫孝
Organizer
第3回肝臓医生物研究会
Place of Presentation
秋田(秋田大学医学部)
Year and Date
2007-01-07
Description
「研究成果報告書概要(和文)」より
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[Presentation] A Novel NF-κB Inhibitor, Dehydroxymethylepoxyquinomicin Suppresses Donor Specific Memory/Effector Cells and Attenuates Development of Cardiac Allograft Vasculopathy.2006
Author(s)
Shinya Ueki, Kenichiro Yamashita, Takeshi Aoyagi, Tomoo Itoh, Tomomi Suzuki, Masahiko Taniguchi, Tsuyoshi Shimamura, Hiroyuki Furukawa, Michitaka Ozaki, Kazuo Umezawa, Satoru Todo.
Organizer
World Transplant Congress
Place of Presentation
米国(Hynes Convention Center)
Year and Date
20060722-26
Description
「研究成果報告書概要(和文)」より
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[Presentation] Control of allograft rejection by appling a novel NF-〓B inhibitor, dehydroxymethylepoxyquinomicin.2006
Author(s)
Kenichiro Yamashita, Shinya Ueki, Takeshi Aoyagi, Sanae Haga, Tomomi Suzuki, Masahiko Taniguchi, Tsuyoshi Shimamura, Hiroyuki Furukawa, Michitaka Ozaki, Kazuo Umezawa, Satoru Todo.
Organizer
World Transplant Congress
Place of Presentation
米国(Hynes Convention Center)
Year and Date
20060722-26
Description
「研究成果報告書概要(和文)」より
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[Presentation] A Novel NF-κB Inhibitor, Dehydroxymethylepoxyquinomicin Suppresses Donor Specific Memory/Effector Cells and Attenuates Development of Cardiac Allograft Vasculopathy.2006
Author(s)
Shinya Ueki, Kenichiro Yamashita, Takeshi Aoyagi, Tomoo Itoh, Tomomi Suzuki, Masahiko Taniguchi, Tsuyoshi Shimamura, Hiroyuki Furukawa, Michitaka Ozaki, Kazuo Umezawa, Satoru Todo
Organizer
World Transplant Congress
Place of Presentation
Boston
Year and Date
20060722-26
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Control of allograft rejection by appling a novel NF-kB inhibitor, dehydroxymethylepoxyquinomicin.2006
Author(s)
Kenichiro Yamashita, Shinya Ueki, Takeshi Aoyagi, Sanae Haga, Tomomi Suzuki, Masahiko Taniguchi, Tsuyoshi Shimamura, Hiroyuki Furukawa, Michitaka Ozaki, Kazuo Umezawa, Satoru Todo.
Organizer
World Transplant Congress
Place of Presentation
Boston
Year and Date
20060722-26
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Impaired Regeneration And Fatal Liver Failure After Resection Of steatotic Liver By Cell Cycle Arrest.2005
Author(s)
Hiroshi Murata, Takahito Yagi, Tetsuya Ogino, Hiroshi Sadamori, Hiroyoshi Matsukawa, Susumu Shinoura, Dong Sheng Sun, Yuzo Umeda, Hiromi Iwagaki, Noriaki Tanaka, Michitaka Ozaki.
Organizer
12th Congress Of The European Society For Organ Transplantation
Place of Presentation
スイス(Geneva, Switzerland)
Year and Date
20051015-19
Description
「研究成果報告書概要(和文)」より
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[Presentation] Impaired Regeneration And Fatal Liver Failure After Resection Of Steatotic Liver By Cell Cycle Arrest.2005
Author(s)
Hiroshi Murata, Takahito Yagi, Tetsuya Ogino, Hiroshi Sadamori, Hiroyoshi Matsukawa, Susumu Shinoura, Dong Sheng Sun, Yuzo Umeda, Hiromi Iwagaki, Noriaki Tanaka, Michitaka Ozaki.
Organizer
12^<th> Congress of The European Society For Organ Transplantation
Place of Presentation
Geneva
Year and Date
20051015-19
Description
「研究成果報告書概要(欧文)」より
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[Presentation] PDK1/Akt activation is crucial in liver regeneration in mouse partial hepatectomy.2005
Author(s)
Sanae Haga, Keita Terui, Hiroshi Inoue, Yasuo Okamoto, Wataru Ogawa, Shin Enosawa, Tadahiro Osada, Moto Fukai, Rumi Igarashi, Hiroyuki Furukawa, Satoru Todo, Michitaka Ozaki.
Organizer
第78回日本生化学会
Place of Presentation
神戸(神戸国際会議揚)
Year and Date
2005-10-20
Description
「研究成果報告書概要(和文)」より
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[Presentation] Michitaka Ozaki. PDK1/Akt activation is crucial in liver regeneration in mouse partial hepatectomy.2005
Author(s)
Sanae Haga, Keita Terui, Hiroshi Inoue, Yasuo Okamoto, Wataru Ogawa, Shin Enosawa, Tadahiro Osada, Moto Fukai, Rumi Igarashi, Hiroyuki Furukawa, Satoru Todo
Organizer
78^<th> Annual Meeting of Japan Society of Biochemistry
Place of Presentation
Kobe
Year and Date
2005-10-20
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Analysis of intracellular signal regulating liver injury and regeneration caused by various factor and possibility of its clinical application.2005
Author(s)
Michitaka Ozaki, Sanae Haga, Wataru Ogawa, Hiroshi Inoue, Hiroshi Murata, Dong Sheng Sun, Hiromi Iwagaki, Rumi Igarashi, Shin Enosawa, Hiroyuki Furukawa, Satoru Todo.
Organizer
12^<th> the Japanese Society for the Research of Hepatic Cells
Place of Presentation
Tokyo
Year and Date
2005-07-09
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Ex vivo stat3 gene transfer prevents liver graft failure and elongates survival in rat fatty liver transplant model.2005
Author(s)
Dong Sheng Sun, Tetsuya Ogino, Takahito Yagi, Hiroshi Sadamori, Hiroyoshi Matsukawa, Susumu Shinoura, Hiroshi Murata, Yuzo Umeda, Hiromi Iwagaki, Noriaki Tanaka, Michitaka Ozaki.
Organizer
ATC2005
Place of Presentation
米国(Washington State Convention & Trade Center)
Year and Date
2005-05-25
Description
「研究成果報告書概要(和文)」より
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[Presentation] Ex vivo stat3 gene transfer prevents liver graft failure and elongates survival in rat fatty liver transplant model.2005
Author(s)
Dong Sheng Sun, Tetsuya Ogino, Takahito Yagi, Hiroshi Sadamori, Hiroyoshi Matsukawa, Susumu Shinoura, Hiroshi Murata, Yuzo Umeda, Hiromi Iwagaki, Noriaki Tanaka, Michitaka Ozaki.
Organizer
ATC2005
Place of Presentation
Seattle
Year and Date
2005-05-25
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Impaired regeneration and fatal liver failure after resection of steatotic liver by cell cycle arrest.2005
Author(s)
Hiroshi Murata, Takahito Yagi, Tetsuya Ogino, Hiroshi Sadamori, Hiroyoshi Matsukawa, Susumu Shinoura, Dong Sheng Sun, Yuzo Umeda, Hiromi Iwagaki, Noriaki Tanaka, Michitaka Ozaki.
Organizer
ATC2005
Place of Presentation
米国(Washington State Convention & Trade Center)
Year and Date
2005-05-24
Description
「研究成果報告書概要(和文)」より
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[Presentation] Impaired regeneration and fatal liver failure after resection of steatotic liver by cell cycle arrest.2005
Author(s)
Hiroshi Murata, Takahito Yagi, Tetsuya Ogino, Hiroshi Sadamori, Hiroyoshi Matsukawa, Susumu Shinoura, Dong Sheng Sun, Yuzo Umeda, Hiromi Iwagaki, Noriaki Tanaka, Michitaka Ozaki.
Organizer
ATC2005
Place of Presentation
Seattle
Year and Date
2005-05-24
Description
「研究成果報告書概要(欧文)」より
