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Pathogenesis and Treatment of beta-Galactosidase-Deficient Knockout Mice

Research Project

Project/Area Number 08457058
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionThe Tokyo Metropolitan Institute of Medical Science

Principal Investigator

SUZUKI Yoshiyuki  The Tokyo Metropolitan Institute of Medical Science, Vice-Director, 副所長 (90010389)

Co-Investigator(Kenkyū-buntansha) FAN Jian-Qiang  The Tokyo Metropolitan Institute of Medical Science, Department of Clinical Gene, 臨床遺伝学, 研究員 (30291157)
SAKURABA Hitoshi  The Tokyo Metropolitan Institute of Medical Science, Department of Clinical Gene, 臨床遺伝学, 室長 (60114493)
MATSUDA Junichiro  National Institute of Health, Department of Veterinary Science, Senior Researche, 獣医科学部, 主任研究官 (60181731)
NAIKI Masaharu  National Institute of Health, Department of Veterinary Science, Director, 獣医科学部, 部長 (10020752)
Project Period (FY) 1996 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥7,700,000 (Direct Cost: ¥7,700,000)
Fiscal Year 1997: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 1996: ¥4,200,000 (Direct Cost: ¥4,200,000)
Keywordsknockout mouse / beta-galactosidase / ganglioside G_<M1> / lysosomal disease / G_<M1>-gangliosidosis / gene therapy / ガングリオンドG_<M1> / ライソゾーム病 / 遺伝子ターゲティング / ガングリオシドGM1
Research Abstract

We succeeded in producing a mouse model of human G_<M1>-gangliosidosis by disruption of the murin beta-galactosidase gene, in order to analyze its pathogenesis and to try therapeutic approaches. Clinically the mutant mouse developed a progressive neurological disease 4 months after birth, manifesting itself as spastic diplegia. They died of severe nervous system dysfunction and extreme emaciation at 7-11 months of age. Neuronal cytoplasmic swelling due to storage of undigested substrates was observed in every area of the central nervous system, and the storage material appeared as membranous cytoplasmic bodies electron microscopically. This morphological change progerssed rapidly between 4 and 8 weeks of age. beta-Galactosidase activity was almost compeltely deficient in all tissues and body fluids examined.
Biochemical analysis revealed a marked storage of ganglioside G_<M1> and its asialo derivative G_<A1>D in the central nervous system and some solid tissues, such as liver and spleen. G_<A1> storage was more remarkable as compared to that in human patients. These results indicated that this model animal is an authentic murine counterpart of human G_<M1>-gangliosidosis. However, there was no bone dysplasia or keratan sulfaturia in these disease mice. Urinary oligosaccharides showed an abnormal pattern on thin-layr chromatography which was similar to that in infantile G_<M1>-gangliosidosis. As an experimental trial, an adenovirus-mediated intravenous injection of beta-galactosidase cDNA was preformed into the mutant newborn mouse. The beta-galactosidase activity was expressed in the central nervous system 2 weeks after injection at the 10% normal lavel. At this stage, storage of G_<M1> and G_<A1> was significantly reduced as compared to animals without treatment. We concluded that the gene introduced in the vascular system has reached the central nervous system through the undeveloped blood-brain barrier in the neonatal period.

Report

(3 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] 滝本 一広、他: "β-ガラクトシダーゼ遺伝子ノックアウトマウスにおけるG_<M1>-ガングリオシドーシスの生化学的検索" 生化学. 33. 39-44 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Matsuda J, et al.: "β-Galactosidase-deficieut mouse as an auiwal wodel of G_<M1>-grnjliosidsis" Glyisuwjugatig. 14. 729-736 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hatsuda J, et al: "Newalogiul wawfestatises of kuockont iniewith β-galactosidase deficiency" Boain Dou. 19. 19-20 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Matsuda J,Suzuki O,Oshima A,Ogura A,Naiki M,Suzuki Y: "Neurological manifestations of knockout mice with beta-galactosidase deficiency" Brain Dev. 19. 9-20 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takiyama N,Itoh K,Shimmoto M,Nishimoto J,Inui K,Sakuraba H,Suzuki Y: "Molecular form and subcellular distribution of acid beta-galactosidase in fibroblasts from patients with G_<M1>-gangliosidosis, Morquio B disease and galactosialidosis" Brain Dev. 19. 126-130 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Matsuda J,Suzuki O,Oshima A,Ogura A,Noguchi Y,Yamamoto Y,Asano T,Takimoto K,Sukeawa K,Suzuki Y,Naiki M: "beta-Galactosidase-deficient mouse as an animal model for G_<M1>-gangliosidosis" Glycoconiugate J. 14. 729-736 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Okamura-Oho Y,Zhang S,Callaha JW,Murata M,Oshima A,Suzuki Y: "Maturation and degradation of beta-galactosidase in the post-Glogi compartment are regulated by cathepsin B and a non-cysteine protease." FEBS Lett. 419. 231-234 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Fukuhara Y,Oshima S,Suzuki Y: "Altered substrate affinity of a mutant beta-galactosidase causing Morquio B disease" Dev Brain Dysfunct. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takiyama N,et al: "Molecular form and subcellular distribution of acid β-galactosidase in fibrobiastes from patients with G_<M1>・gaugliosidasic,Morgio β oli seace" Brain & Development. 19. 126-130 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Matsuda J,et al: "β-Galactosidase-deficient mouse as an animal model of G_<M1>-ganglissidosis" Glycocoujugate Journal. 14. 729-736 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Okamura-Oho Y,et al: "Maturation and digoadation of β-galactosidabe in the pose-Golgi compartment are regulated by carbepsin β and a non-cysteine protease" FEBS Letters. 419. 231-234 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Novo Mde LP,et.al.: "CSF ganglid Aide analysis using a highly sehsitie enrymeimmunastining wexhod in Rets syudrowe and ofher pen rologic discsres" J Tokyo Women′s med Cell. 66. 117-127 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Matsuda J,et al: "Neusological mainfostatins of knockout mice with β-galactosidase efewonu" Brain Der. 19. 19-20 (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Matsuda J,at al: "β-Galactosidare difiuiat Knockout mause or an animal modl for G_<Mz>-grugdi 3,silosis" Glycoroujugate J. (in press). (1997)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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