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Development of humanized NOG mice reconstituted with human hepatocytes and their applications in drug discovery and infectious disease research.

Research Project

Project/Area Number 17300136
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Laboratory animal science
Research InstitutionCentral Institute for Experimental Animals

Principal Investigator

SUEMIZU Hiroshi  Central Institute for Experimental Animals, Laboratory Head, バイオメディカル研究部, 室長 (40332209)

Co-Investigator(Kenkyū-buntansha) NAKAMURA Masato  Tokai University, School of Medicine, Professor, 医学部, 教授 (00164335)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥15,200,000 (Direct Cost: ¥15,200,000)
Fiscal Year 2006: ¥6,500,000 (Direct Cost: ¥6,500,000)
Fiscal Year 2005: ¥8,700,000 (Direct Cost: ¥8,700,000)
Keywordsimmunodeficient NOG mice / liver regeneration / hepatocytes transplantation
Research Abstract

The aim of this study, which was designed to establish a drug evaluation model and infectious disease model, was "to develop a reconstituted mouse with human hepatocytes". The research plan consisted of the following three steps, and the results at each step are described.
First step : Development of genetically modified mice with sustained hepatic injury.
We established a transgenic mouse (Alb-HSV-Tk), which carries the herpes simplex virus thymidine kinase gene with an albumin enhancer and promoter, to induce hepatocyte specific cell injury by ganciclovir (GCV). Two-hundred and eight pups were obtained by DNA microinjection experiments and we succeeded in obtaining 9 founder mice that showed positive reactions in the first screening by the PCR genotyping test.
Second step : Induction of hepatocyte specific cell injury by GCV administration.
Transgenic pups were obtained from nine Alb-HSV-Tk founders, and the ability to induce hepatic injury by GCV injection was examined. According to the results, elevated levels of AST and ALT were observed only in the Tg-Alb-HSV-Tk #7-2 line (Tg-Tk#7-2). Furthermore, Tg-Tk#7-2 showed apparent jaundice in the ears. Histological investigation of the mouse liver revealed a number of abnormalities, including hepatocyte vaculation and hepatocyte megalocytosis.
Third step : Application in a drug evaluation study with reconstituted mice with human hepatocytes.
Unfortunately, the third step could not be completed within the planned period. The main reason was the sterility in the Tg-Tk#7-2 line, which made large-scale production using in vitro fertilization and embryo transplantation techniques impossible, and drastically delayed our production plan. However, we obtained a few Tg-Tk#7-2 NOG mice, and have already started a human hepatocyte transplantation experiment with weekly evaluations for signs of humanization (Hu-Liver NOG). The Hu-Liver NOG mouse will be a useful model to facilitate the evaluation of drug efficacy and pharmacokinetics.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (14 results)

All 2006 2005 Other

All Journal Article (14 results)

  • [Journal Article] Gallbladder small cell carcinoma Xenograft established by serial transplantation in nude mice.2006

    • Author(s)
      Nishime C.
    • Journal Title

      Anticancer Res. 26(1A)

      Pages: 79-83

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary 2005 Annual Research Report
  • [Journal Article] Poor outcome of patients with pulmonary adenocarcinoma showing decreased E-cadherin combined with increased S100A4 expression.2006

    • Author(s)
      Miyazaki N.
    • Journal Title

      Int J Oncol 6

      Pages: 1369-1374

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Poor outcome of patients with pulmonary adenocarcinoma showing decreased E-cadherin combined with increased S100A4 expression.2006

    • Author(s)
      Miyazaki N.
    • Journal Title

      Int J Oncol. 28

      Pages: 1369-74

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Gallbladder small cell carcinoma Xenograft established by serial transplantation in nude mice.2006

    • Author(s)
      Nishime C.
    • Journal Title

      Anticancer Res. 26

      Pages: 79-83

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Poor outcome of patients with pulmonary adenocarcinoma showing decreased E-cadherin combined with increased S100A4 expression.2006

    • Author(s)
      Miyazaki N.
    • Journal Title

      Int Oncol 6

      Pages: 1369-74

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Establishment of novel embryonic stem cell lines derived from the common marmoset (Callithrix jacchus).2005

    • Author(s)
      Sasaki E.
    • Journal Title

      Stem Cells. 23(9)

      Pages: 1304-1313

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] S100A4 expression with reduced E-cadherin expression predicts distant metastasis of human malignant melanoma cell lines in the NOD/SCID/gammaCnull (NOG) mouse model.2005

    • Author(s)
      Ikoma N.
    • Journal Title

      Oncol Rep. 14(3)

      Pages: 633-637

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary 2005 Annual Research Report
  • [Journal Article] 免疫不全マウスを用いたヒトがんモデルの作製2005

    • Author(s)
      末水 洋志
    • Journal Title

      血液・腫瘍科 51(1)

      Pages: 104-112

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Establishment of novel embryonic stem cell lines derived from the common marmoset (Callithrix jacchus).2005

    • Author(s)
      Sasaki E.
    • Journal Title

      Stem Cells. 23

      Pages: 1304-13

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] S100A4 expression with reduced E-cadherin expression predicts distant metastasis of human malignant melanoma cell lines in the NOD/SCID/gammaCnull (NOG) mouse model.2005

    • Author(s)
      Ikoma N.
    • Journal Title

      Oncol Rep. 14

      Pages: 633-7

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Development of human cancer model using immunodeficient mice.2005

    • Author(s)
      Suemizu H.
    • Journal Title

      Ketsueki・Shuyouka 51

      Pages: 104-112

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Establishment of novel embryonic stem cell lined derived from the common marmoset (Callithrix jacchus).2005

    • Author(s)
      Sasaki E.
    • Journal Title

      Stem Cells. 23(9)

      Pages: 1304-1313

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Identification of a key molecular regulator of liver metastasis in human pancreatic carcinoma using a novel quantitative model of metastasis in NOD/SCID/γ_c^<null> (NOG) mice.

    • Author(s)
      Suemizu H.
    • Journal Title

      Int J Oncol (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Identification of a key molecular regulator of liver metastasis in human pancreatic carcinoma using a novel quantitative model of metastasis in NOD/SCID/γc^<null> (NOG) mice.

    • Author(s)
      Suemizu H.
    • Journal Title

      Int J Oncol. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary

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Published: 2005-04-01   Modified: 2016-04-21  

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