| Project/Area Number |
10557064
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Neurology
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| Research Institution | Tokyo Metropolitan Organization for Medical Research, Tokyo Metropolitan Institute for Neuroscience (1999-2000)
Tokyo Metropolitan Institute for Neuroscience (1998) |
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Principal Investigator |
UCHIHARA Toshiki Tokyo Metropolitan Organization for Medical Research, Tokyo Metropolitan Institute for Neuroscience, Staff Scientist, 東京都神経科学総合研究所, 研究員 (10223570)
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| Co-Investigator(Kenkyū-buntansha) |
YOKOTA Takanori Tokyo Medical and Dental University, Faculty of Medicine, Lecturer, 医学部, 講師 (90231688)
INOUE Keizo University of Tokyo, Faculty of Pharmaceutics, Professor, 薬学部, 教授 (30072937)
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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 |
¥5,200,000 (Direct Cost: ¥5,200,000)
Fiscal Year 2000: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1999: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1998: ¥2,800,000 (Direct Cost: ¥2,800,000)
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| Keywords | alpha-tocopherol transfer protein / vitamin E deficiency / knock out / hereditary ataxias / プルキンエ細胞 |
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| Research Abstract |
The first autopsy case with progressive ataxia and retinitis pigmentosa associated with a mutation of the gene coding for alpha-tocopherol transfer protein (aTTP) was investigated. In addition to retinal lesion and dying-back type degeneration in the posterior column of the spinal cord, comparable to those reported in cases or animal model with deficiency of vitamin E, mild degeneration was noted in the cerebellar cortex. Mouse model with deleted aTTP was generated, where massive accumulation of lipofuscin was noted in the anterior horn cells of the spinal cord in addition to posterior column lesion. Because these spinal lesions were exaggerated or attenuated by excess intake or deficiency of vitaminE, respectively, effects of deleted a TTP gene is mediated by lowered vitaminE concentration in the tissue. On the other hand, vitaminE concentration in the cerebellum of the autopsy case mentioned above is normalized except for the cerebellum after long term administration of vitamin E.If the metabolic pathway of vitamin E in the cerebellum is different, a mutation of aTTP gene may have affected it and lead to cerebellar degeneration. Because similar cerebellar lesion was not detectable in model mice with deleted a TTP gene, molecular pathway involving aTTP and its regional difference should be further investigated. Hereditary ataxias of other origins were also investigated with special attention to neuronal intranuclear inclusions (NIIs). Immunolocalization of ataxin-2, -3 was investigated in a series of autopsy brains including various CAG repeat disorders and neuronal intranuclear hyaline inclusion disease (NIHID). It was found that the presence of ataxin-2 or -3 in the NIIs was not specific for SCA2 or SCA3, respectively. We invented dual intensification technique for double-labeled immunofluorescence, which is now proved to be very effective for immunohistochemistry applicable to a wide range of disorders including vitamineE and aTTP abnormality.
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