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Molecular Approach to an Amyloidosis by Using Gene Targeting

Research Project

Project/Area Number 07044242
Research Category

Grant-in-Aid for international Scientific Research

Allocation TypeSingle-year Grants
SectionJoint Research
Research InstitutionYamanashi Medical University

Principal Investigator

MAEDA Shuichiro  Yamanashi Medical University Professor, 医学部, 教授 (10117244)

Co-Investigator(Kenkyū-buntansha) EPISKOPOU Vasso  Royal Postgraduate Medical School, Mouse Embryology, マウス発生学研究室, 室長
SARAIVA Maria.J.M  Institute de Ciencias Biomedicas, Universidade do Porto, 医科学研究所, 教授
BUXBAUM J.N.  ニューヨーク大学, 医学部, 教授
COSTANTINI F  コロンビア大学, 医学部, 教授
GOTTESMAN M.  コロンビア大学, 癌研究所, 所長
SHIMADA Kazunori  Research Institute for Microbial Diseases, Osaka Universiy, 微生物病研究所, 教授 (40037354)
GOTTESMAN Max E  Institute of Cancer Research, Columbia University
COSTANTINI Franklin D  Department of Genetics and Development, Columbia University
BUXBAUM Joel N  Laboratory of Molecular Pathogenesis, New York Department of Veterans Affairs Me
Project Period (FY) 1995 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥8,000,000 (Direct Cost: ¥8,000,000)
Fiscal Year 1996: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1995: ¥4,000,000 (Direct Cost: ¥4,000,000)
Keywordsamyloidosis / transthyretin / mouse model of human disease / familial amyloidotic polyneuropathy / gene targeting / embryonic Stem cells / serum amyloid P component / transgenic mouse / トランスサイレチン(プレアルブミン) / ジーンターゲティング
Research Abstract

1, The introduction of the human mutant transthyretin (ttr) gene (6.0-hMet 30) which is responsible for familial amyloidotic polyneuropathy (FAP) into the TTR-deficient (ttr^<-/->) mice significantly increased their depressed serum levels of thyroxine (T_4) and plasma retinol-binding protein (RBP), suggesting that human TTR Met 30 binds T_4 and RBP in vivo.The T_4-binding ability of human TTR Met 30 was confirmed by the analysis of T_4-binding proteins in the sera of ttr^<-/-> transgenic mice expressing 6.0-hMet 30. The T_4-binding studies also demonstrated the presence of hybrid tetramers between mouse and human TTR subunits in the ttr^<+/+> transgenic mice expressing 6.0-hMet 30.
2, The gene encoding serum amyloid P component (SAP) was disrupted in CCE embryonic stem (ES) cells by homologous recombination. After injection of the ES cell clones into C57BL/6 host blastocysts two germ-line chimeras were obtained. The chimeras were bred with C57BL/6 females and the mice heterozygous for t … More he disrupted sap allele were intercrossed. Genotyping of the resulting progeny of 30 different litters with an average litter size of 7 showed that live-born mice homozygous for the disrupted sap allele (sap^<-/->) were recovered at the predicted frequency. The absence of SAP in the serum of sap^<-/-> mice was confirmed by Western blot analysis. The SAP-deficient mice display no obvious phenotypic abnormalities and their fertility is normal. To investigate the relationship between SAP and amyloid deposition, we asked if experimental AA amyloidosis can be induced in the SAP-deficient mice. AA amyloid deposition occurred in the absence of SAP.We are now in the process of comparing the onset and progression of AA amyloid deposition in the sap^<-/-> and wild-type mice
3, Using a novel gene targeting procedure, we introduced an amyloidogenic point mutation (TTR Met 30) into the endogenous ttr gene in ES cells. After injection of the ES cell clones into C57BL/6 host blastocysts several chimeras were obtained. The chimeras are now being bred with C57BL/6 femals. Less

Report

(3 results)
  • 1996 Annual Research Report   Final Research Report Summary
  • 1995 Annual Research Report
  • Research Products

    (27 results)

All Other

All Publications (27 results)

  • [Publications] Horie,K.,Maeda,S.,Nishiguchi,S.,Gottesman,M.and Shimada,K.: "A replacement vector used to introduce subtle mutations into mouse genes." Gene. 166. 197-204 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Nagata,Y.,Tashiro,F.,Yi,S.,Murakami,T.,Maeda,S.,Takahashi,K.,Shimada,K.,Okamura,H.and Yamamura,K.: "A 6-kb upstream region of the human transthyretin gene can direct developmental,tissue-specific,and quantitatively normal exprssion in transgenic mouse." J.Biochem.117. 169-175 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kato,G.,Maeda,S.: "Novel phosphorylation at a mitotic site,serine 75,in human pp^<60C-SRC> from unsynchronized human tumor cells having a spherical morphology." Biochem.Biophys.Res.Commun.216. 619-629 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Wei,S.,Episkopou,V.,Piantedosi,R.,Maeda,S.,Shimada,K.,Gottesman,M.E.and Blaner,W.S.: "Studies on the metabolism of retinol and retinol-binding protein in transthyretin-deficient mice produced by homologous recombination." J.Biol.Chem.270. 866-870 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] 前田秀一郎・横井恭子: "家族性アミロイドポリニューロパチーに近似した疾患モデルマウスの作出" 蛋白質核酸酵素. 40. 2204-2213 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] 前田秀一郎: "常染色体性優性の遺伝病、家族性アミロイドポリニューロパチーの遺伝子診断" 医学のあゆみ. 174. 484-489 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] 前田秀一郎: "遺伝子治療研究のための疾患モデル動物" 最新医学(増刊号). 50. 1740-1749 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Maeda S.: "Mouse models of amyloidoses generated by transgenesis." Amyloid : Int J Exp Clin Invest. 3. 214-215 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kohno K.,Palha J.A.,Miyakawa K.,Saraiva M.J.M.,Ito S.,Mabuchi T.,Blaner W.S.,Iijima H.,Tsukahara S.,Episkopou V.,Gottesman M.E.,Shimada K.,Takahashi K.,Yamamura K.,and Maeda S.: "Analysis of amyloid deposition in a transgenic mouse model of homozygous familial amyloidotic polyneuropathy." Am.J.Pathol. (印刷中). (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] 前田秀一郎: "家族性アミロイドポリニューロパチー" 実験医学別冊・Bio Science用語ライブラリー・遺伝子病. 74-76 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] 前田秀一郎: "家族性アミロイドポリニューロパチー" 病理と臨床. 14(臨時増刊). 18-21 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Horie, K., Maeda, S., Nishiguchi, S., Gottesman, M.and shimada, K.: "A replacement vector used to introduce subtle mutations into mouse genes." Gene. 166. 197-204 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Nagata, Y., Tashiro, F., Yi, S., Murakami, T., Maeda, S., Takahashi, K., Shimada, K., Okamura, H.and Yamamura, K.: "A 6-kb upstream region of the human transthyretin gene can direct developmental, tissue-specific, and quantitatively normal exprssion in transgenic mouse." J.Biochem.117. 169-175 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kato, G., Maeda, S.: "Novel phosphorylation at a mitotic site, serine 75, in human pp^<60C-SRC> from unsynchronized human tumor cells having a spherical morphology." Biochem.Biophys.Res.Commun.216. 619-629 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Wei, S., Episkopou, V., Piantedosi, R., Maeda, S., Shimada, K., Gottesman, M.E.and Blaner.W.S.: "Studies on the metabolism of retinol and retinol-binding protein in transthyretin-deficient mice produced by homologous recombination." J.Biol.Chem.270. 866-870 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Maeda S.: "Mouse models of amyloidoses generated by transgenesis." Amyloid : Int J Exp Clin Invest. 3. 214-215 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kohno K., Palha J.A., Miyakawa K., Saraiva M.J.M., Ito S., Mabuchi T., Blaner W.S., Iijima H., Tsukahara S., Episkopou V., Gottesman M.E., Shimada K., Takahashi K., Yamamura K., and Maeda S.: "Analysis of amyloid deposition in a transgenic mouse model of homozygous familial amyloidotic polyneuropathy." Am.J.Pathol. (in press). (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kohno,K et al.: "Analysis of amyloid deposition in a transgenic mouse model of homozygous familial amyloidotic polyneuropathy." Am.J.Pathol. (印刷中). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Maeda S.: "Mouse models of amyloidoses generated by transgenesis." Amyloid:Int J Exp Clin Invest. 3. 214-215 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 前田秀一郎: "家族性アミロイドポリニューロパチー" 実験医学別冊・Bio Science用語ライブラリー・遺伝子病. 74-76 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 前田秀一郎: "家族性アミロイドポリニューロパチー" 病理と臨床. 14(臨時増刊). 18-21 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Horie,K.,Maeda,S.,Nishiguchi,S.,Gottesman,M.and Shimada,K.: "A replacement vector used to introduce subtle mutations into mouse genes." Gene. 166. 197-204 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Kato,G.,Maeda,S.: "Novel phosphorylation at amitotic site,serine 75,in human pp60^<C-SRC> from unsynchronized human tumor cells having aspherical morphology." Biochem.Biophys. Res. Commun.216. 619-629 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 前田秀一郎・横井恭子: "家族性アミロイドポリニューロパチーに近似した疾患モデルマウスの作出" 蛋白質核酸素酵素. 40. 2204-2213 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 前田秀一郎: "常染色体優性の遺伝病、家族性アミロイドポリニューロパチーの遺伝子診断" 医学のあゆみ. 174. 484-489 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 前田秀一郎: "遺伝子治療研究のための疾患モデル動物" 最新医学. 50(増刊号). 1740-1749 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Wei,S.,Episkopou,V.,Piantedosi,R.,Maeda,S.,Shimada,K.,Gottesman,M.E.and Blaner,W.S.: "Studies on the metabolism of retinol and retinolbinding protein in transthyretin-deficient mice produced by homologous recombination." J. Biol. Chem.270. 866-870 (1995)

    • Related Report
      1995 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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