| Project/Area Number |
11694290
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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 |
Molecular biology
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
NAKABEPPU Yusaku Kyusu Univ., Med. Inst. Bioreg., Prof., 生体防御医学研究所, 教授 (30180350)
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| Co-Investigator(Kenkyū-buntansha) |
TOMINAGA Yohei Kyusu Univ., Med. Inst. Bioreg., Res. Ass., 生体防御医学研究所, 助手 (90304823)
SAKUMI Kunihiko Kyusu Univ., Med. Inst. Bioreg., Res. Ass., 生体防御医学研究所, 助手 (50211933)
FURUICHI Masato Kyusu Univ., Med. Inst. Bioreg., Res. Ass., 生体防御医学研究所, 助手 (70199420)
TSUZUKI Teruhisa Kyusu Univ., Grad. Sch. Med. Sci., Prof., 大学院・医学系学府, 教授 (40155429)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥9,100,000 (Direct Cost: ¥9,100,000)
Fiscal Year 2001: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2000: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1999: ¥3,300,000 (Direct Cost: ¥3,300,000)
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| Keywords | Reactive Oxigen Species / 8-oxoguanine / 2-hydroxyadenine / mitochondria / neurodegeneration / Parkinson's disease / amyotrophic lateral sclerosis / carcinogenesis / 基質認識 / 自然突然変異 / 肺腫瘍 / 遺伝子欠損マウス |
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| Research Abstract |
For living organisms, the most fundamental biological function is maintaining the integrity of their genomic DNAs harboring the genetic information and transmitting them precisely from cell to cell, as well as from parents to their offsprings. The genomic DNA and its precursor nucleotides, are always in danger of oxidation by free radicals such as superoxide or NO produced during the oxygen respiration and other normal metabolisms. Various oxidized bases and nucleotides are formed in DNA or nucleotide pools by the free radicals, and such oxidative DNA damage may cause mutations or cell death if they are not repaired. Mutations may induce cancers, and cell death may be related to various degenerative disorders such as neurodegenarative diseases.
In this project, we have aimed to unveil the molecular mechanisms protecting genomic integrity from damage caused by free radicals. We have been especially focusing on neuronal cell death as a consequence of oxidative damages in non-proliferative cells, as well as on cancer that is believed to be a consequence of such damages in proliferative cells.
We have identified and characterized four human enzymes, (1) oxidized purine nucleoside triphosphatase (MTH1), (2) 2-hydroxyadenine/adenine DNA glycosylase (MYH), (3) 8-oxoguanine DNA glycosylase (OGG1), and (4) novel AP endonuclease (APE2). Characterization of knockout mice for each gene revealed that spontaneous accumulation of oxidative DNA damage causes increased occurrence of mutation as well as carcinogenesis. We also found that such oxidative DNA damage accumulates in degenerative neurons along with altered expression of the protective enzymes in patients with neurodegenerative diseases, suggesting that oxidative DNA damage may be involved in neurodegeneration.
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