| Project/Area Number |
04404029
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| Research Category |
Grant-in-Aid for General Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Nagoya University |
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Principal Investigator |
OZAWA Takayuki Faculty of Medicine, Univ of Nagoya, Professor, 医学部, 教授 (80022771)
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| Co-Investigator(Kenkyū-buntansha) |
HAYAKAWA Mika Faculty of Medicine, Univ of Nagoya Assistant Professor, 医学部, 助手 (10238090)
TANAKA Masashi Faculty of Medicine, Univ of Nagoya Associate professor, 医学部, 助教授 (60155166)
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| Project Period (FY) |
1992 – 1994
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| Project Status |
Completed (Fiscal Year 1994)
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| Budget Amount *help |
¥29,000,000 (Direct Cost: ¥29,000,000)
Fiscal Year 1994: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1993: ¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 1992: ¥19,000,000 (Direct Cost: ¥19,000,000)
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| Keywords | mitochondrial DNA / 8-hydroxydeoxyguanosine / aging / point mutations / oxidative stress / cardiomyopathy / deleted mtDNA / reactive oxygen species / 遺伝子欠失 / 蛍光PCR-SSCP法 / 発癌物質 / 心毒性 / ミトコンドリア病 / 老化 / 酸化的DNA損傷 / ラジカル脆弱性 |
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| Research Abstract |
To elucidate the contribution of mitochondrial abnormality both to the pathogenesis of mitochondrial disease and to the degenerative changes associated with aging, we developed a rapid method for analyzing the entire sequence of the mitochondrial genome. The analysis revealed both mit^- mutations, which alter amino acids that are highly conserved among species, and syn^- mutations, which alter phylogenetically conserved nucleotides in tRNA and rRNA genes. The life spans of patients who possessed both mit^- and syn^-mutations were significantly shorter than those of patients with only either mit^- or syn^- mutations (Lancet 345 : 189,1995). The analysis of the four-fold degeneration sites in the coding regions revealed that the nucleotide substitutions occur asymmetrically with respect to the strands (Genomics 22 : 327-335,1994). We also demonstrated that age-dependent exponential accumulation of deleted mtDNA and 8-hydroxydeoxyguanosine. The PCR detection system with 180 primer pairs revealed that a patient with mitochondrial cardiomyopathy who died at 19 years old possessed numerous deleted mtDNAs in the amounts comparable to those in aged individuals (BBRC202 : 102-110,1995). Teses results suggest that the combination of maternally inherited mtDNA mutations (mit^- and syn^-) accelerates the accumulation of mtDNA mutations (deletions and point mutations) in somatic cells, and thereby increases the production of reactive oxygen species from mitochondria, leading to aggravation of mitochondrial diseases and degenerative changes associated with aging.
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