| Project/Area Number |
10680784
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Laboratory animal science
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| Research Institution | National Institute of Infectious Diseases |
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Principal Investigator |
MATSUDA Junichiro National Institute of Infectious Diseases, Department of Veterinary Science, Senior Researcher, 獣医科学部, 主任研究官 (60181731)
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| Co-Investigator(Kenkyū-buntansha) |
OGURA Atsuo National Institute of Infectious Diseases, Department of Veterinary Science, Chief, 室長 (20194524)
TAKIMOTO Kazuhiro National Institute of Infectious Diseases, Division of Experimental Animals Research, Researcher, 動物管理室, 研究員 (70280766)
SUZUKI Osamu National Institute of Infectious Diseases, Department of Veterinary Science, Senior Researcher, 主任研究官 (70235935)
大島 章弘 国立感染症研究所, 獣医科学部, 客員研究員
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| Project Period (FY) |
1998 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2000: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1999: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1998: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | Mouse / Disease model / Transgenic / Lysosomal disease / β-Galactosidase / Gangliosidosis / Neurodegenerative disease / Gene therapy / ガングリオシドーシズ |
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| Research Abstract |
GM1-gangliosidosis is a progressive neurological disease caused by a deficiency of lysosomal β-galactosidase(β-Gal) and is classified into three clinical forms : infantile, juvenile and adult. We recently generated β-Gal knockout(KO) mice as an authentic model of GM1-gangliosidosis. In this study, we conducted biochemical analysis of the model mice and demonstrated that the accumulation of gangliosides GM1 and asialoGM1 occurred as early as 1-2 weeks of age in their brains. We also generated the C57BL/6 congenic strain of KO mice and revealed the some differences in. storage materials between original crossbred and congenic strains. To evaluate the gene therapy using adeno-associated virus(AAV) vector for GM1-gangliosisosis mice, we injected AAV containing human β-Gal into the mouse brain and demonstrated the enzyme activities were detected only in a limited area for one month. We introduced the wild-type human β-Gal transgene into β-Gal KO mice in order to rescue their GM1-gangliosidosis phenotypes. We also introduced into β-Gal KO mice the mutant human β-Gal transgenes with R201C and I51T amino acid substitutions, which were common for juvenile and adult GM1-gangliosidoses, respectively. Three types of transgenes containing the β-actin promoter/human β-Gal cDNA (wild-type, R201C or I51T) were used. Transgenics were bred with β-Gal KO mice, and the resulting three types of KO/transgenic mice lacked mouse β-Gal gene but had human β-Gal (wild-type, R201C or I51T) transgene. As expected, the wild-type human β-Gal transgene could rescue the mouse GM1-gangliosidosis. KO/transgenic mice expressing mutant human β-Gals might be useful for the studies of pathogenesis and treatment of GM1-gangliosidosis with residual enzyme activities.
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