| Project/Area Number |
13670154
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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 |
Pathological medical chemistry
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| Research Institution | Tokyo Metropolitan Institute of Gerontology |
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Principal Investigator |
SHIRASAWA Takuji Tokyo Metropolitan Institute of Gerontology, Department of Molecular Gerontology, Head., 東京都老人総合研究所・分子老化研究グループ, 副参事研究員 (80226323)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Aging / Posttranslational modification / Isoaspartic acid / PIMT / Knockout mice / Transgenic mice / Neurodegeneration / Gene therapy / 翻訳後装飾 / イソアスパラギン酸メチル転移酸素 / アルツハイマー病 / 加齢 |
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| Research Abstract |
Protein-L-isoaspartyl methyltransfearase (PIMT) plays a physiological role in the repair of damaged proteins containing isoaspartyl residues (IsoAsp). In previous studies, we showed that PIMT-deficient mice developed a fatal epileptic seizure associated with the accumulation of damaged proteins in the brain. In the present study, we generated PIMT transgenic (Tg) mice to investigate whether the exogenous expression of PIMT could improve the symptoms associated with PIMT-deficiency. Rescue experiments showed that Tg expression of PIMT effectively cured the PIMT-deficient mice. Biochemically, a higher expression level of transgene led to the effective repair of damaged proteins in vivo. Although a lower level of expression caused an accumulation of damaged proteins in a partially-rescued line, the mice survived. Furthermore, We administered an adeno-PIMT vector into the brain of PIMT-deficient mice at embryonic day 14.5 by an exoutero method to assess the biological effects in vivo. The result showed that adeno-PIMT improved the symptoms of PIMT-deficient mice in vivo, but only partially repaired IsoAsp in damaged proteins. The gene therapy presented in this report provided a better prognosis for the survival of PIMT-deficient mice than the previously reported anti-epileptic drug therapy.
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