| Project/Area Number |
08457196
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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 | 一般 |
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| Research Field |
Neurology
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| Research Institution | NIPPON MEDICAL SCHOOL INSTITUTE OF GERONTOLOGY |
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Principal Investigator |
OHTA Shigeo NIPPON MEDICAL SCHOOL INSTITUTE OF GERONTOLOGY,PROFESSOR, 老人病研究所, 教授 (00125832)
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| Co-Investigator(Kenkyū-buntansha) |
ISHIBASHI Yoshitomo NIPPON MEDICAL SCHOOL INSTITUTE OF GERONTOLOGY RESEARCH ASSISTANT, 老人病研究所, 助手
KAMINO Kojin NIPPON MEDICAL SCHOOL INSTITUTE OF GERONTOLOGY RESEARCH ASSISTANT, 老人病研究所, 助手 (40307955)
ASHO Sadamitu NIPPON MEDICAL SCHOOL INSTITUTE OF GERONTOLOGY ASSOCIATE PROFESSOR, 老人病研究所, 助教授 (70167914)
若尾 りか 日本医科大学, 老人病研究所, 助手 (20277586)
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| Project Period (FY) |
1996 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥7,900,000 (Direct Cost: ¥7,900,000)
Fiscal Year 1998: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1997: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1996: ¥4,500,000 (Direct Cost: ¥4,500,000)
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| Keywords | mitochondria / mitochondria encephalomyopathy / apoptosis / tRNA / gene therapy / Fas / Bcl-2 family / Bax / ミトコンドリア病 / エネルギー代謝 / Bcl-2 / ミトコンドリアDNA / bcl-2 / ミトコンドリア機能低下 / 治療 |
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| Research Abstract |
Several mutations in the mitochondrial genome are responsible for mitochondrial encephalomyopathy. It is in principle impossible to cure the disease by introducing normal genes into affected cells, because of the multicopic mitochondrial genome, and because of greater propagation of the mutant genome than of the normal one. Thus, if the cells accumulated with mutant mtDNA can be eliminated by apoptosis, the mutant mtDNA was removed with the cells themselves, and expectedly compensate by growing the normal cells. For this purpose, we found that Fas gene responds against mitochondrial dysfunction. In addition, three genes that express more by the mitochondrial dysfunction are isolated by the differential display method. One is a kind DNA ligase and another belongs to the DNA modifying enzyme, and the other is novel gene.
In studies on apoptosis, structure of a regulator of apoptosis, Bcl-x was determined by x-ray crystallography and the structure of Bax, an inducer of apoptosis was modeled by the analogy modeling method. The structure of Bax was speculated to have a pore forming domain, and turned out to be responsible for apoptosis. Without the dimer forming domains with the other BcI-2 family proteins, only the pore forming domain induced apoptosis. This finding indicates that the pore forming domain should be a good protein for inducing apoptosis in the cells accumulated with the mutant mitochondrial DNA.
Furthermore, in order to find the molecular mechanism of the pathogenesis of mitochondrial encephalomyopathy, the mutant mitochondrial tRNAs were purified and determined the nucleotide sequences, including modified bases. We found that the first letters of the anticodon are commonly deficient in the modification. This result suggest that this defect on the modification causes misincorporahion of amino acid into the proteins encoded by the mitochondria genome, indicating the novel method to cure the disease by forced modification of anticodon.
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