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Molecular Pathogenesis of a Dominantly Inherited Disorder-Analysis by Using a Mouse Model of Disorder

Research Project

Project/Area Number 02454494
Research Category

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

Allocation TypeSingle-year Grants
Research Field Human genetics
Research InstitutionKUMAMOTO UNIVERSITY

Principal Investigator

MAEDA Shuichiro  Kumamoto Univ.School of Medicine, Dept.of Biochemistry, Assoc.Prof., 医学部, 助教授 (10117244)

Co-Investigator(Kenkyū-buntansha) SETOYAMA Chiaki  Kumamoto Univ.School of Medicine, Dept.of Biochemistry, Lecturer, 医学部, 講師 (60040250)
Project Period (FY) 1990 – 1992
Project Status Completed (Fiscal Year 1992)
Budget Amount *help
¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1992: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1991: ¥1,000,000 (Direct Cost: ¥1,000,000)
KeywordsAmyloidosis / Serum amyloid P component / Mouse model of disorder / Transgenic mouse / Transthyretin / Gene targeting / Familial amyloidotic polyneuropathy / Dominantly inherited disorder / トランスサイレチン(プレアルブミン) / 相同DNA間組換え / 遺伝子標的組み込み / 胚性幹細胞 / 遺伝性疾患 / アミロイド-シス / キメラマウス / プレアルブミン / 遺伝性標的組み込み / 遺伝子疾患
Research Abstract

(1) We examined whether sustained high serum levels of serum amyloid P component (SAP) induced by repeated intraperitoneal injections of E.coli lipopolysaccharide (LPS) enhance the amyloid deposition in the transgenic mouse model of familial amyloidotic polyneuropathy (FAP). No significant difference was detected in the onset, progression, and tissue distribution of amyloid deposition between the LPS-stimulated and unstimulated transgenic mice.
(2) We constructed a sequence replacement vector to introduce an inactivating neo^r marker into the mouse genomic transthyretin (ttr) gene by homologous recombination. The targeting vector consisted of a 5.9 kb DNA fragment derived from the mouse ttr genomic locus and the 1.1 kb neo^r gene from pMC1Neo. A counter-selectable HSV-tk gene was placed at the end of the long region of homology. This vector was electroporated into cultured mouse embryonic stem (ES) cells, which were subsequently selected with G418 and gancyclovir. Among the 132 colonies obtained, 6 homologous recombinants were identified by PCR and Southern blotting.
(3) These ES cells were used to generate chimeric mice by injection into blastocysts. One of these chimeras has shown germline transmission of the disrupted ttr gene. Heterozygous mice were crossed to try to generate homozygotes. Homozygous TTR-deficient mice were found at the expected Mendelian frequencies and appeared to be phenotypically normal. However, levels of serum retinol, retinol-binding protein, and thyroid hormone are significantly depressed in the mutant mice. We are now in the process of establishing transgenic mouse lines carrying the human mutant ttr gene which is responsible for FAP in the homozygous mutant background.

Report

(4 results)
  • 1992 Annual Research Report   Final Research Report Summary
  • 1991 Annual Research Report
  • 1990 Annual Research Report
  • Research Products

    (33 results)

All Other

All Publications (33 results)

  • [Publications] Yi,S.et al.: "Systemic amyloidosis in transgenic mice carrying the human mutant transthyretim (Met 30) gene:Pathologic similarlity to human familial amyloidotic polyneuropathy,type I." Am J Pathol. 138. 403-412 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ohuchi,K.et al.: "A transgenic mouse line developed to express human amyloidogenic transthyretin cDNA in the brain." Biochem Int. 23. 809-817 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Tashiro,F.et al.: "Role of serum amyloid P component for systemic amyloidosis in transgenic mice carrying human mutant transthyretin gene." Gerontology. 37(Supple 1). 56-62 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Murakami,T.et al.: "Effect of serum amyloid P component level on transthyretin-derived amyloid deposition in a transgenic mouse model of familial amyloidotic polyneuropathy." Am J Pathol. 141. 451-456 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Murakami,T.et al.: "A novel transthyretin mutation associated with familial amyloidotic polyneuropathy." Biochem Biophys Res Commun. 182. 520-526 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Murakami,T.et al.: "A novel transthyretin mutation at position 30 (Leu for Val) associated with familial amyloidotic polyneuropathy." Biochem Biophys Res Commun. 187. 397-403 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Episkopou,V.et al.: "Disruption of the transthyretin gene results in mice with depressed levels of plasma retinol and thyroid hormone." Proc Natl Acad Sci USA. 90. 2375-2379 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yamamura,K.et al.: "Transgenic mouse model for human genetic diseases." Mol Repro Develop. 36. 248-250 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Maeda,S.et al.: "in Familial Amiloidotic Polyneuropathy and Other Transthyretin Related Disorders,Molecular structures and evolution of mammalian pentraxin genes." Editions Arquivos de Medicina 3,Porto (Costa,P.P.,de Freitas.A.F.and Saraiva,M.J.M.,eds.), 6 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Nishiguchi,S.et al.: "in Familial Amiloidotic Polyneuropathy and Other Trans-thyretin Related Disorders,Transcriptional regulation of mammalian pentraxin genes." Editions Arquivos de Medicina 3,Porto(Costa,P.P.,de Freitas.A.F.and Saraiva,M.J.M.,eds), 4 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yi, S.et al.: "Systemic amyloidosis in transgenic mice carrying the human mutant transthyretin (Met 30) gene : Pathologic similarlity to human familial amyloidotic polyneuropathy, type I" Am J Pathol. 138. 403-412 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ohuchi, K.et al.: "A transgenic mouse line developed to express human amyloidogenic transthyretin cDNA in the brain" Biochem Int. 23. 809-817 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Tashiro, F.et al.: "Role of serum amyloid P component for systemic amyloidosis in transgenic mice carrying human mutant transthyretin gene" Gerontology. 37 (Suppl 1). 56-62 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Murakami, T.et al.: "Effect of serum amyloid P component level on transthyretin-derived amyloid deposition in a transgenic mouse model of familial amyloidotic polyneuropathy" Am J Pathol. 141. 451-456 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Murakami, T.et al.: "A novel transthyretin mutation associated with familial amyloidotic polyneuropathy" Biochem Biophys Res Commun. 182. 520-526 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Murakami, T.et al.: "A novel transthyretin mutation at position 30 (Leu for Val) associated with familial amyloidotic polyneuropathy" Biochem Biophys Res Commun. 187. 397-403 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Episkopou, V.et al.: "Disruption of the transthyretin gene results in mice with depressed levels of plasma retinol and thyroid hormone" Proc Natl Acad Sci USA. 90. 2375-2379 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yamamura, K.et al.: "Transgenic mouse model for human genetic diseases" Mol Repro Develop. 36. 248-250 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Maeda, S.et al.: Molecular structures and evolution of mammalian pentraxin genes. in Familial Amiloidotic Polyneuropathy and Other Transthyretin Related Disorders, Editions Arquivos de Medicina 3,215-220 Porto 1990 (Costa, P.P., de Freitas.A.F.and Saraiva, M.J.M., eds.),

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Nishiguchi, S.et al.: in Familial Amiloidotic Polyneuropathy and Other Transthyretin Related Disorders, Editions Arquivos de Medicina 3,221-224 Porto 1990 (Costa, P.P., de Freitas.A.F.and Saraiva, M.J.M., eds.)25HC02 : Transcriptional regulation of mammalian pentraxin genes,

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Murakami.T.et al.: "Effect of Serum Amyloid P Component Level on Transthyretin-derived Amyloid Deposition in a Transgenic Mouse Model of Familial Amyloidotic Polyneuropathy" Am.J.Pathol.141. 451-456 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Murakami.T.et al.: "A Novel Transthyretin Mutation at Potition 30 (Leu for Val)Associated with Familial Amyloidotic Polyneuropathy" Biochem.Biophys.Res.Commun.187. 397-403 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Episkopou,V.et al.: "Disruption of the Transthyretin Gene Results in Mice with Depressed Levels of Plasma Retinol and Thyroid Hormone" Proc.Natl.Acad.Sci.U.S.A.

    • Related Report
      1992 Annual Research Report
  • [Publications] Yamamura,K.et al.: "in Molecular Approaches to the Study and Treatment of Human Diseases,Analysis of the Pathological Process of DominantDisease:Familial Amyloidotic Polyneuropathy" (Yoshida,T.O. & Wilson,J.M.,eds.)Elsevier Science Publishers,B.V.,Amsterdam, 8 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Ohuchi,K.et al.: "A Transgenic Mouse Line Developed to Express Human Amyloidogenic Transthyretin cDNA in the Brain" Biochem.Int.23. 809-817 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Tashiro,F.et al.: "Role of Serum Amyloid P Component for Systemic Amyloidosis in Transgenic Mice Carrying Human Mutant Transthyretin Gene" Gerontology. 37. 56-62 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Murakami,T.et al.: "A Novel Transthyretin Mutation Associated with Familial Amyloidotic Polyneuropathy" Biochem.Biophys.Res.Commun.182. 520-526 (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Murakami,T.et al.: "Investigation of Effect of Serum Amyloid P Component Level on TransthyretinーDerived Amyloid Deposition in a Transgenic Mouse Model of Familial Amyloidotic Polyneuropathy" Am.J.Pathol.

    • Related Report
      1991 Annual Research Report
  • [Publications] Murakami,T.et al.: "in Amyloid and Amyloidosis 1990,An Attempt to Study the Role of Serum Amyloid P Component in the Formation of Amyloid Deposits in a Transgenic Mouse Model of Familial Amyloidotic Polyneuropathy" (Natvig.J.B.,Fφrre,φ.,Husby,G.,Husebekk,A.,Skogen,B.,Sletten,K.and Westermark,P.,eds.),Kluwer Academic Publishers,Dordrecht, 4 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Yi,S.et al.: "Systemic amyloidosis in transgenic mice carrying the human mutant transthyretin (Met30) gene:pathologic similarity to human familial amyloidotic polyneuropathy,type I" Am.J.Pathol.138. 403-412 (1991)

    • Related Report
      1990 Annual Research Report
  • [Publications] Ohuchi,K.et al.: "A transgenic mouse line developed to express human amyloidogenic transthyretin cDNA in the brain" Biochem.Int.

    • Related Report
      1990 Annual Research Report
  • [Publications] Araki,S.et al.: "in CharctotーMarieーTooth Disorders: Pathophysiology,Molecular Genetics,and Therapy,Neurology and Neurobiology 53,Molecular Genetics of Familial Amyloidotic Polyneuropathy Type I" Lovelace,R.E.& Shapiro,H.K.,eds.WileyーLiss,New York, 6 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Yamamura,K.et al.: "in Molecular Mechanisms of Aging,Transgenic mouse model of an autosomal dominant disease: Familial amyloidotic polyneuropathy" Beyreuther,K.& Schettler,G.,eds.SpringerーVerlag,Heidelberg, 9 (1990)

    • Related Report
      1990 Annual Research Report

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Published: 1991-04-01   Modified: 2016-04-21  

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