Development of hepatitis C virus suicide therapy employing the viral protease
| Project/Area Number |
23659393
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Gastroenterology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
KOIKE Kazuhiko 東京大学, 医学部附属病院, 教授 (80240703)
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| Project Period (FY) |
2011 – 2012
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| Project Status |
Completed (Fiscal Year 2012)
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| Budget Amount *help |
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2011: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
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| Keywords | ウイルス / 癌 / 肝炎 / 感染症 |
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| Research Abstract |
Hepatitis C virus (HCV) inactivates the innate immunity pathway, which leads from retinoic acid-inducible gene (RIG)-I to IFNss-induction, by the specific digestion of IFN promoter-stimulator (IPS)-1 on the mitochondrial outer membrane, by the action of viral protease NS3/4a. This results in the malfunction of IFN-activation system in the liver, which is considered to play a central role in the persistence of HCV infection and the resistance to IFN treatment. We have attempted to establish “HCV suicide thrapy” in that sending the transcription module (HCV-protease activated module; CPAM, inactivation form) into the liver by the utilization of NS3/4a protease. It is supposed that inactivated form of the CPAM is activated by the action of NS3/4a protease in HCV-infected cells, leading to the activation of intrahepatic innate immunity and complete eradication of HCV from the liver.In 2011, we constructed the CPAM module that carries IRF7 in conjunction with mitochondrial transfer signal and NS3/4a protease digestion motif (c503 amino acid residues), which derived from IPS-1.
In 2012, The CPAM was introduced into Huh-7 cells in which the HCV subgenomic replicon replicates and NS3/4a protease is produced. IRF7 was actually transferred from the cytoplasm to nuclei. In addition, we constructed the recombinant adenovirus that carries the CPAM. This was introduced into Huh-7 cells that support the replication of HCV JFH-1 strain to evaluate the load-reducing effect of CPAM. The JFH-1 loads weresignificantly reduced in CPAN- introduced Huh-7 cells compared to control Huh-7 cells, demonstrating the proof of concept of this HCV suicide therapy using NS3/4a protease.
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Report
(3 results)
Research Products
(27 results)
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[Journal Article] MiRNA-140 acts as a liver tumor suppressor by controlling NF-κB activity via directly targeting Dnmt1 expression2013
Author(s)
Takata A, Otsuka M, Yoshikawa T, Kishikawa T, Hikiba Y, Obi S, Goto T, Kang YJ, Maeda S, Yoshida H, Omata M, Asahara H, Koike K
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Journal Title
Hepatology
Volume: 57
Pages: 162-170
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[Journal Article] Increased activity of serum mitochondrial isoenzyme ofcreatine kinase in hepatocellular carcinoma patients predominantly with recurrence2012
Author(s)
Soroida Y, Ohkawa R, Nakagawa H, Satoh Y, Yoshida H, Kinoshita H, Tateishi R, Masuzaki R, Enooku K, Shiina S, Sato T, Obi S,Hoshino T, Nagatomo R, Okubo S, Yokota H, Koike K, Yatomi Y, Ikeda H
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Journal Title
J Hepatol
Volume: 57(2)
Pages: 330-336
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[Journal Article] Systemic combination therapy of intravenous continuous 5-fluorouracil and subcutaneous pegylated interferon alfa-2a for advanced hepatocellular carcinoma.2012
Author(s)
Uchino K, Obi S, Tateishi R, Sato S, Kanda M, Sato T, Arano T, Enooku K, Goto E, Masuzaki R, Nakagawa H, Asaoka Y, Kondo Y, Yamashiki N, Goto T, Shiina S, Omata M, Yoshida H, Koike K
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Journal Title
J Gastroenterol
Volume: 22438097
Pages: 1-5
NAID
Related Report
Peer Reviewed
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[Journal Article] Serum level of adiponectin and the risk of liver cancer development in chronic hepatitis C patients2011
Author(s)
Arano T, Nakagawa H, Tateishi R, Ikeda H, Uchino K, Enooku K, Goto E, Masuzaki R, Asaoka Y, Kondo Y, Goto T, Shiina S, Omata M, Yoshida H, Koike K
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Journal Title
Int J Cancer
Volume: 129(9)
Pages: 2226-2235
Related Report
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[Journal Article] Characteristics of hepatocellular carcinoma nodules newly detected by computed tomography during arteriography and arterial portography: preliminary report of a randomized controlled trial2011
Author(s)
Ohki T, Tateishi R, Akahane M, Shiina S, Yamashiki N, Mikami S, Enooku K, Goto E, Masuzaki R, Kondo Y, Goto T, Inoo S, Ohtomo K, Omata M, Yoshida H, Koike K
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Journal Title
Hepatol Int
Volume: 22020826
Pages: 1-5
Related Report
Peer Reviewed
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[Journal Article] Direct differentiation of hepatic cells from human induced pluripotent stem cells using a limited number of cytokines2011
Author(s)
Takata A, Otsuka M, Kogiso T, Kojima K, Yoshikawa T, Tateishi R, Kato N, Shiina S, Yoshida H, Omata M, Koike K
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Journal Title
Hepatol Int
Volume: 21484132
Pages: 1-5
Related Report
Peer Reviewed
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[Presentation] Hepatitis C virus NS5A protein impairs cytokine production through toll-like receptor signaling pathway in mouse liver2011
Author(s)
Takeya Tsutsumi, Seiko Shinzawa, Koji Goto, Hidetaka Fujinaga, Hideyuki Miyoshi, Yoshizumi Shintani, Kyoji Moriya, Hiroshi Yotsuyanagi, Tetsuro Suzuki, Yoshiharu Matsuura, Kazuhiko Koik
Organizer
HCV2011
Place of Presentation
Seattle, USA
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