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Novel animal models for hereditary diseases using human hepatocytes transplanted chimeric mice and vaculovirus

Research Project

Project/Area Number 26420796
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Biofunction/Bioprocess
Research InstitutionHiroshima University

Principal Investigator

Chayama Hiromi  広島大学, 医歯薬保健学研究院(医), 准教授 (70572329)

Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywordsゲノム編集 / ヒト肝細胞キメラマウス / 遺伝性肝疾患 / 遺伝性肝疾患モデル
Outline of Final Research Achievements

In this study, I established two type of CRISPR-Cas9 systems using vaculovirus vectors that work to knock out or mutate causative genes of hemochromatosis, porphyria, glycogenosis, amino acid metabolism abnormality, urea cycle disorder, constitutional jaundice, fibrotic cystic liver disease and Wilson’s disease. I transfected theses constructs into HEK293 cells and harvested vaculoviruses. However, when I inoculated HuH7 cells and HepG2 cells with the vaculoviruses, the cell growths’ were seriously inhibited. From these results, I decided to improve vaculovirus vectors. Now I confirming whether the targeted genome editing was occurred using the improved CRISPR-Cas9 systems. Further experiments are necessary. I will establish in vitro hereditary liver diseases models using human primary hepatocytes derived from human hepatocytes transplanted chimeric mice and in vivo models using human hepatocytes transplanted chimeric mice with these CRISPR-Cas9 systems.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Research-status Report
  • 2014 Research-status Report
  • Research Products

    (22 results)

All 2017 2016 2015 2014 Other

All Journal Article (17 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 17 results,  Open Access: 7 results,  Acknowledgement Compliant: 4 results) Presentation (3 results) (of which Int'l Joint Research: 2 results) Remarks (2 results)

  • [Journal Article] Development of a novel site-specific pegylated interferon beta for antiviral therapy for chronic hepatitis B.2017

    • Author(s)
      Tsuge M, Uchida T, Hiraga N, Kan H, Makokha GN, Abe-Chayama H, Miki D, Imamura M, Ochi H, Hayes CN, Shimozono R, Iwamura T, Narumi H, Suzuki T, Kainoh M, Taniguchi T, Chayama K.
    • Journal Title

      Antimicrob Agents Chemother.

      Volume: 印刷中 Issue: 6 Pages: 61-61

    • DOI

      10.1128/aac.00183-17

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Interferon alpha treatment stimulates interferon gamma expression in type I NKT cells and enhances their antiviral effect against hepatitis C virus.2017

    • Author(s)
      Miyaki E, Hiraga N, Imamura M, Uchida T, Kan H, Tsuge M, Abe-Chayama H, Hayes CN, Makokha GN, Serikawa M, Aikata H, Ochi H, Ishida Y, Tateno C, Ohdan H, Chayama K.
    • Journal Title

      PLoS One.

      Volume: 12 Issue: 3 Pages: e0172412-e0172412

    • DOI

      10.1371/journal.pone.0172412

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Usefulness of humanized cDNA-uPA/SCID mice for the study of hepatitis B virus and hepatitis C virus virology.2017

    • Author(s)
      Uchida T, Imamura M, Kan H, Hiraga N, Hayes CN, Tsuge M, Abe-Chayama H, Aikata H, Makokha GN, Miki D, Ochi H, Ishida Y, Tateno C, Chayama K.
    • Journal Title

      J Gen Virol.

      Volume: 印刷中 Issue: 5 Pages: 1040-1047

    • DOI

      10.1099/jgv.0.000726

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Antiviral effects of anti-HBs immunoglobulin and vaccine on HBs antigen seroclearance for chronic hepatitis B infection.2016

    • Author(s)
      Tsuge M, Hiraga N, Uchida T, Kan H, Miyaki E, Masaki K, Ono A, Nakahara T, Abe-Chayama H, Zhang Y, Naswa MG, Kawaoka T, Miki D, Imamura M, Kawakami Y, Aikata H, Ochi H, Hayes CN, Chayama K.
    • Journal Title

      J Gastroenterol.

      Volume: 51 Pages: 1073-1080

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Highly multiplexed CRISPR-Cas9-nuclease and Cas9-nickase vectors for inactivation of hepatitis B virus.2016

    • Author(s)
      Sakuma T, Masaki K, Abe-Chayama H, Mochida K, Yamamoto T, Chayama K.
    • Journal Title

      Genes Cells.

      Volume: 21 Issue: 11 Pages: 1253-1262

    • DOI

      10.1111/gtc.12437

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Elimination of HCV via a non-ISG-mediated mechanism by vaniprevir andBMS-788329 combination therapy in human hepatocyte chimeric mice.2016

    • Author(s)
      Uchida T, Hiraga N, Imamura M, Yoshimi S, Kan H, Miyaki E, Tsuge M, Abe H, Hayes CN, Aikata H, Ishida Y, Tateno C, Ellis JD, Chayama K.
    • Journal Title

      Virus Res.

      Volume: 213 Issue: 1 Pages: 62-68

    • DOI

      10.1016/j.jinf.2015.09.038

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Human Cytotoxic T Lymphocyte-Mediated Acute Liver Failure and Rescue by Immunoglobulin in Human Hepatocyte Transplant TK-NOG Mice.2015

    • Author(s)
      Uchida T., Hiraga N., Imamura M., Tsuge M., Abe H., Hayes C.N., Aikata H., Ishida Y., Tateno C., Yoshizato K., Ohdan H., Murakami K. and Chayama K.
    • Journal Title

      Journal of Virology

      Volume: 89 Issue: 19 Pages: 10087-96

    • DOI

      10.1128/jvi.01126-15

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Rapid, Sensitive, and Accurate Evaluation of Drug Resistant Mutant (NS5A-Y93H) Strain Frequency in Genotype 1b HCV by Invader Assay2015

    • Author(s)
      Satoshi Yoshimi, Hidenori Ochi, Eisuke Murakami, Takuro Uchida, Hiromi Kan, Sakura Akamatsu, C. Nelson Hayes, Hiromi Abe, Daiki Miki, Nobuhiko Hiraga, Michio Imamura, Hiroshi Aikata, Kazuaki Chayama.
    • Journal Title

      PLOS ONE

      Volume: 10 Issue: 6 Pages: e0130022-e0130022

    • DOI

      10.1371/journal.pone.0130022

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Long term persistence of NS5A inhibitor-resistant hepatitis C virus in patients who failed daclatasvir and asunaprevir therapy.2015

    • Author(s)
      Yoshimi S, Imamura M, Murakami E, Hiraga N, Tsuge M, Kawakami Y, Aikata H, Abe H, Hayes CN, Sasaki T, Ochi H, Chayama K.
    • Journal Title

      J Med Virol.

      Volume: 87 Issue: 11 Pages: 1913-1920

    • DOI

      10.1002/jmv.24255

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Novel Robust in Vitro Hepatitis B Virus Infection Model Using Fresh Human Hepatocytes Isolated from Humanized Mice.2015

    • Author(s)
      Ishida Y, Yamasaki C, Yanagi A, Yoshizane Y, Fujikawa K, Watashi K, Abe H, Wakita T, Hayes CN, Chayama K, Tateno C.
    • Journal Title

      Am J Pathol.

      Volume: 185 Issue: 5 Pages: 1275-1285

    • DOI

      10.1016/j.ajpath.2015.01.028

    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Journal Article] Association between variants in the interferon lambda 4 locus and substitutions in the hepatitis C virus non-structural protein 5A.2015

    • Author(s)
      Akamatsu S, Hayes CN, Ochi H, Uchida T, Kan H, Murakami E, Abe H, Tsuge M, Miki D, Akiyama R, Hiraga N, Imamura M, Aikata H, Kawaoka T, Kawakami Y, Chayama K.
    • Journal Title

      J Hepatol.

      Volume: 63 Issue: 3 Pages: 554-563

    • DOI

      10.1016/j.jhep.2015.03.033

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Differences in serum microRNA profiles in hepatitis B and C virus infection.2015

    • Author(s)
      Akamatsu S, Hayes CN, Tsuge M, Miki D, Akiyama R, Abe H, Ochi H, Hiraga N, Imamura M, Takahashi S, Aikata H, Kawaoka T, Kawakami Y, Ohishi W, Chayama K.
    • Journal Title

      J Infect.

      Volume: 70 Issue: 3 Pages: 273-287

    • DOI

      10.1016/j.jinf.2014.10.017

    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Journal Article] The effects of bisphosphonate zoledronic acid in hepatocellular carcinoma, depending on mevalonate pathway.2015

    • Author(s)
      Honda Y, Takahashi S, Zhang Y, Ono A, Murakami E, Shi N, Kawaoka T, Miki D, Tsuge M, Hiraga N, Abe H, Ochi H, Imamura M, Aikata H, Chayama K.
    • Journal Title

      J Gastroenterol Hepatol.

      Volume: 30 Issue: 3 Pages: 619-627

    • DOI

      10.1111/jgh.12715

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] New insight into the enhanced effect of pegylated interferon-α.2014

    • Author(s)
      Abe H, Hayes CN, Chayama K.
    • Journal Title

      Hepatology.

      Volume: 60 Issue: 4 Pages: 1435-1437

    • DOI

      10.1002/hep.27269

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Emergence of resistant variants detected by ultra-deep sequencing after asunaprevir and daclatasvir combination therapy in patients infected with hepatitis C virus genotype 1.2014

    • Author(s)
      Kosaka K, Imamura M, Hayes CN, Abe H, Hiraga N, Yoshimi S, Murakami E, Kawaoka T, Tsuge M, Aikata H, Miki D, Ochi H, Matsui H, Kanai A, Inaba T, Chayama K.
    • Journal Title

      J Viral Hepat.

      Volume: 22 Issue: 2 Pages: 158-165

    • DOI

      10.1111/jvh.12271

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ribavirin dose reduction during telaprevir/ribavirin/peg-interferon therapy overcomes the effect of the ITPA gene polymorphism.2014

    • Author(s)
      Akamatsu S, Hayes CN, Tsuge M, Murakami E, Hiraga N, Abe H, Miki D, Imamura M, Ochi H, Chayama K; Hiroshima Liver Study Group.
    • Journal Title

      J Viral Hepat.

      Volume: 22 Issue: 2 Pages: 166-174

    • DOI

      10.1111/jvh.12275

    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Journal Article] Human microRNA hsa-miR-1231 suppresses hepatitis B virus replication by targeting core mRNA.2014

    • Author(s)
      Kohno T, Tsuge M, Murakami E, Hiraga N, Abe H, Miki D, Imamura M, Ochi H, Hayes CN, Chayama K.
    • Journal Title

      J Viral Hepat.

      Volume: 21 Issue: 4 Pages: 369-375

    • DOI

      10.3851/imp2777

    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Presentation] Analysis of the effect on HBV by genome editing using CRISPR/Cas9 system2016

    • Author(s)
      Keiichi Masaki, Hiromi Abe, Tetsushi Sakuma, Masataka Tsuge, Michio Imamura, Nelson Hayes, Hiroshi Aikata, Takashi Yamamoto, Kazuaki Chayama
    • Organizer
      AASLD2016
    • Place of Presentation
      アメリカ・ボストン
    • Year and Date
      2016-11-11
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Analysis of the effect on HBV life cycle by HBV genome editing using two different CRISPR/Cas9 systems.2015

    • Author(s)
      Abe H, Masaki K, Sakuma T, Tsuge M, Hiraga N, Imamura M, Hayes CN, Aikata H, Yamamoto T, Chayama K.
    • Organizer
      The 66th AASLD Annual Meeting
    • Place of Presentation
      San Francisco, USA.
    • Year and Date
      2015-11-13
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] HCV感染におけるIFNL4の多型の違いによるIFN-λsの発現量とインターフェロン投与前後のインターフェロン誘導遺伝子の発現量の関係2014

    • Author(s)
      阿部弘美, 三木大樹, 平賀伸彦, 今村道雄, 柘植雅貴, 小林知樹, 河岡友和, 川上由育, 相方浩, 越智秀典, 茶山一彰
    • Organizer
      第50回日本肝臓学会総会
    • Place of Presentation
      東京
    • Year and Date
      2014-05-29 – 2014-05-30
    • Related Report
      2014 Research-status Report
  • [Remarks] 広島大学大学院医歯薬保健学研究科消化器・代謝内科

    • URL

      http://shounai.hiroshima-u.ac.jp/

    • Related Report
      2016 Annual Research Report
  • [Remarks] 広島大学大学院医歯薬保健学研究院応用生命科学部門消化器・代謝内科学ホームページ

    • URL

      http://home.hiroshima-u.ac.jp/naika1/

    • Related Report
      2014 Research-status Report

URL: 

Published: 2014-04-04   Modified: 2018-03-22  

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