| Project/Area Number |
06404042
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | NAGOYA UNIVERSITY |
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Principal Investigator |
MAEDA Kenji Nagoya University School of Medicine, Professor, 医学部, 教授 (90023853)
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| Co-Investigator(Kenkyū-buntansha) |
MIYATA Toshio Tokai University School of Medicine, Associate Professor, 総合医学研究所, 講師 (10222332)
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| Project Period (FY) |
1994 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥30,500,000 (Direct Cost: ¥30,500,000)
Fiscal Year 1997: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1996: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1995: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1994: ¥25,500,000 (Direct Cost: ¥25,500,000)
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| Keywords | dialysis-related amyloidosis / Advanced glycation end-products / beta2-microglobuli / uraemia / oxidative stress / 腎不全 / 酸化ストレス / Redox imbalance / AGEs / カルボキシメチルリジン / メイラード反応 / β2ミクログロブリン / AGEsレセプター / カルボキシルメチルリジン / Advanced Glycation End Products:AGEs / アマドリ構造 / 抗AGEs抗体 |
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| Research Abstract |
beta2-Microglobulin is a major constituent of amyloid fibrils in dialysis-related amyloidosis (DRA), a serious complication leading to bone and joint destruction in long-term haemodialysis patients. However, the molecular pathogenesis of this complication remains unknown. Intact beta2-microglobulin seems an unlikely contributor to the pathogenesis, because no difference in the plasma levels of intact beta2-microglobulin has yet been found between haemodialysis patients with and without this complication. Some investigators have therefore focused on the modification of this molecule. Our studies have revealed a new modification of beta2-microglobulin in amyloid fibrils-the advanced glycation end-products (AGEs) formed by a non-enzymatic reaction between sugar aldose and protein. Our further study has suggested that the interaction of AGE-midified beta2-microglobulin in long-lived amyloid fibrils with monocytes/macrophages gives a plausible explanation for part of the mechanism of bone and joint destruction in DRA.
The cause of long-term complications of uraemia are yet to be fully elucidated. It has recently been demonstrated that renal failure is associated with a dramatic elevation of AGEs. A mild rise of AGEs is associated with normal ageing. In uremia, the rise of AGEs is even more marked than in diabetics and is associated with a variety of tissue disorders. AGE accumulation in uraemia does not result from hyperglycemia. Identification of its cause as well as of the involved precursors should contribute to the understanding of uraemic toxcity and open new therapeutic approaches. In course of our recent studies, we propose the hypothesis that AGE generation is enhanced an increased oxidative stress associated with uraemia. Under these conditions, a variety of compounds, both related and unrelated to glucose, may contribute to the advanced glycoxidation of proteins.
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