| Project/Area Number |
06557064
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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 | 試験 |
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| Research Field |
Kidney internal medicine
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
DOI Toshio Kyoto University, Faculty of Medicine, Assisiant Professor, 医学研究科, 講師 (60183498)
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| Co-Investigator(Kenkyū-buntansha) |
HARA Seijiro Shionogi Research Laboratones, Researcher, 研究員
HAKAMATA Yasuhiro Kyoto University, Faculty of Medicine, Instructor, 医学研究科, 助手 (30261233)
YOKODE Masayuki Kyoto University, Faculty of Medicine, Assistant Professor, 医学研究科, 講師 (20252447)
FUKATSU Atsushi Aichi Medical University, Faculty of Medicine, Assistant Professor, 医学部, 講師 (90247685)
上田 之彦 京都大学, 医学部, 助手 (70252434)
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| Project Period (FY) |
1994 – 1996
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| Project Status |
Completed (Fiscal Year 1996)
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| Budget Amount *help |
¥12,300,000 (Direct Cost: ¥12,300,000)
Fiscal Year 1996: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1995: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1994: ¥8,000,000 (Direct Cost: ¥8,000,000)
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| Keywords | diabetic nephropathy / glomerulonephritis / advanced glycation endproducts / type IV collagen / DNA binding protein / chaperone / HSP 47 / ribozyme / 非酵素的糖化終末産物 / 受容体 / 転写因子 / シャベロン蛋白 / アンチセンス / 糖尿病 / 腎症 / メサンギウム細胞 / 強発現 |
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| Research Abstract |
Diabetic nephropathy is one of the most important diseases for cause of endstage kidney disease. The pathogenesis and treatment of the disease are critical for medical and social problems. Diabetic complications are mediated by advanced glycation endproducts (AGE) which produced by long-term reaction between proteins and high glucose condition. This study was designed to establish the model of diabetic nephropathy and to study the mechanism and the prevention of disease progress. We analyzed knockout mice for apolipoprotein E that developed the progressive glomerulosclerosis in association with glomerular hypertrophy. Mesangial cells had a low affinity receptor for AGE (RAGE) and increased the synthesis of extracellular matrix including type IV collagen. This reaction was mediated by specific DNA binding protein for promoter of type IV collagen (Alp145), which had multifunctions including DNA replication factor C and DNA binding proteins for promoter of angiotensinogen. The expression
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of Alp145 was correlated with glomerular sclerosis and cell proliferation in vivo model. Furthermore, we applied the hammerhead ribozyme for targeting RAGE and established a stable cell line that produced RAGE-specific ribozyme. The induction of type IV mRNA by AGE on mesangial cell was inhibited by RAGE-specific ribozyme. Heat shock protein 47 (HSP47) is a collagen-specific chaperone that has a major role during the biosynthesis and secretion of procollagen molecules. The expression of HSP47 increased in parallel with the expression of collagens during the progression of glomerulosclerosis in renal ablation rats. The administration of antisense oligonucleotides against HSP47 at the induction of anti-thy-1 glomerulonephritis markedly suppressed the increased production of collagens and attenuated the histological manifestations of desease. This study provides to establish the model for typical glomerulosclerosis, to determine the mechanisms of disease progression, and to further develop new strategy for prevention of disease progression. Less
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