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Molecular analysis of TSK mouseas a model of scleroderma

Research Project

Project/Area Number 10044275
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field General medical chemistry
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

HONJO Tasuku  Dept. of Med. Chem., Kyoto Univ. Fac. Med. professor, 医学研究科, 教授 (80090504)

Co-Investigator(Kenkyū-buntansha) NISHIMURA Hiroyuki  Dept. of Med. Chem., Kyoto Univ. Fac. Med. assistant professor, 医学研究科, 助手 (30314181)
CONSTANTIN A. Bona  京都大学, 医学部微生物学教室, 教授
CONSTANTIN A  マウントサイナイ医科大学, 医学部, 教授
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥7,100,000 (Direct Cost: ¥7,100,000)
Fiscal Year 1999: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 1998: ¥3,600,000 (Direct Cost: ¥3,600,000)
Keywordsprogressive systemic sclerosis / TSK mice / fibrillin 1 / mutated fibrillin 1 / 進行性全身強皮症 / fibrillin 1 / 変異型fibrillin 1
Research Abstract

A mouse model of human progressive systemic scleroderma, TSK mice, develop scleroderma and pulmonary emphysema. We have succeeded in identify a mutated form of fibrillin 1 gene, which encodes a intrageneic duplication form. We demonstrated that this mutated form of fibrillin 1 was secreted in culture supernatant of COS7 cells by transient transfection assay. To examine whether this mutated form of fibrillin 1 causes the phenotype of scleroderma, transgenic mice of it under chicken β-actin promoter were generated. The mice developed the thickness of skin along with increased content of hydroxyproline as they aged but not emphysema. And they had autoantibododies for topoisomerase I but not for fibrillin. In addition, wild type mice, which was immunized with expression vector containing the mutated fibrillin 1 as a DNA vaccination method, also developed transient skin thickness with increased hydroxyproline content and autoantibodies for fibrillin. This method did not induce emphysema either. Taken all together, it was concluded that the mutated fibrillin 1 is a causative gene for parts of the phenotypes observed in TSK mice. There are two possibilities for the reason why the emphysema was not caused by this mutated fibrillin 1. First, expression level of the mutated fibrillin 1 was not sufficient for the manifestation of emphysema. Second, there was another responsible gene or genes very close to the mutated fibrillin 1. To test these possibility, another transgenic mice are being generated under keratin 14 promoter or elongation factor promoter.

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] Bona,C.A., Murai,C., Casares,S., Kasturi,K., Nishimura,H., Honjo,T., And Matsuda,F.: "Structure of the mutant fibrillin-l gene in the tight skin (TSK) mouse"DNA Res.. 4. 267-271 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nishimura,H., Minato,N., Nakano,T., And Honjo,T.: "Immunological studies on PD-l deficient mice: implication of PD-l as a negative regulator for B cel responses"Int. Immunol.. 10. 1563-1572 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Saito,S., Nishimura,H., Brumeanu,T.D., Casares,S., Stan,A.C., Honjo,T., And Bona,C.A.: "Characterization of mutated protein encoded by partially duplicated fibrillin-l gene in tight skin (TSK) mice"Mol. Immunol.. 36. 169-176 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nishimura,H., Nose,M., Hiai,H., Minato,N., And Honjo,T.: "Development of lips-like auto-immune disease by disruption of the PD-l gene encoding an ITIM motif-carrying immunoreceptor"Immunity. 11. 141-151 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Saito,S., Nishimura,H., Phelps,R., Wolf,I., Suzuki,M. Honjo,T., And Bona,C.: "Induction of skin fibrosis in mice expressing a mutated fibrillin-l gene"J. Clin. Invest.. (submitted).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Bona, C. A., Murai, C., Casares, S., Kasturi, K., Nishimura, H., Honjo, T., and Matsuda, F.: "Structure of the mutant fibrillin-1 gene in the tight skin (TSK) mouse."DNA Res.. 4. 267-271 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nishimura, H., Minato, N., Nakano, T., and Honjo, T.: "Immunological studies on PD-1 deficient mice : implication of PD-1 as a negative regulator for B cell responses."Int. Immunol. 10. 1563-1572 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Saito, S., Nishimura, H., Brumeanu, T.-D., Casares, S., Stan, A. C., Honjo, T., and Bona, C. A.: "Characterization of mutated protein encoded by partially duplicated fibrillin-1 gene in tight skin (TSK) mice."Mol. Immunol. 36. 169-176 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nishimura, H., Nose, M., Hiai, H., Minato, N., and Honjo, T.: "Development of lups-like autoimmune disease by disruption of the PD-1 gene encoding an ITIM motif-carrying immuno-receptor"Immunity. 11. 141-151 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Saito, S., Nishimura, H., Phelps, R., Wolf, I., Suzuki, M., Honjo, T., and Bona, C: "Induction of skin fibrosis in mice expressing a mutated Fibrillin-1 gene"J. Clin. Invest. (submitted.).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Saito S.,Nishimura H.,Phelps R.,Wolf I.,Suzuki M.,Honjo T.and Bona C.: "Induction of skin fibrosis in mice expressing a mutated Fibrillin-1 gene"J. Clin. Invest. Submitted.

    • Related Report
      1999 Annual Research Report
  • [Publications] Saito,S.,Nishimura,H.,Brumeanu,T.D.,Casares,S.Stan,A.C.,Honjo,T.,Bona,C.A.: "Characterization of Mutated Protein Encoded by Partially Duplicated Fibrillin-1 Gene in Tight Skin(TSK)Mice." Mol.Immunol.(in press).

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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