| Project/Area Number |
10470054
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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 |
Experimental pathology
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| Research Institution | Hirosaki University |
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Principal Investigator |
YAGIHASHI Soroku Hirosaki University, Faculty of Medicine, Professor, 医学部, 教授 (40111231)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAGISHI Shinichiro Hirosaki University, Faculty of Medicine Instructor, 医学部, 助手 (80301026)
WADA Ruichi Hirosaki University, Faculty of Medicine Instructor, 医学部, 助手 (20260408)
KUROTAKI Hidekachi Hirosaki University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (40215108)
八木橋 法登 弘前大学, 医学部, 講師 (10250622)
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| Project Period (FY) |
1998 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2001: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1999: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | Diabetes mellit / Tissue injury / Complications / Polyol pathway / Aldose reductase / Advanced glycation end-products / Microangiopathy / Neuropathy / トランスジェニックマウス / グリケーション / 活性酸素 / AGE(後期糖化生成物) / 細胞傷害 / 酸化ストレス / 血管障害 |
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| Research Abstract |
Drastic increase in diabetic population poses serious problems in the medical care and cost m modern world. There is an urgent need for clarification of the cause of diabetic complications and for the establishment of effective prevention. The aim of the author's project is to explore the mechanisms of tissue injury in diabetic complication-prone organs; peripheral nerve and kidney and to establish effective means to prevent these abnormalities. To determine the possible role of polyol pathway, we used transgenic mice which express human aldose reductase (hAR), a key enzyme of polyol pathway and compared with non-transgenic animals. Production of advanced glycation end-products (AGE) was also attempted to examine the in vivo effects of AGE on the tissue damage in kidney and peripheral nerve. Furthermore, autopsy materials from diabetic patients were exploited to identify the overexpression of AR as well as AGE in the injured site in diabetic organs. As a result, we confirmed that AR is a major determinant for the onset and severity of diabetic complications in transgenic mice as well as in human diabetic patients. It was also confirmed that AGE had a pathogenetic role in the microvascular injury in diabeteic condition and excessive oxidative stress mediates the AGE-induced tissue injury. These tissue injuries are the major process not only in the diabetic peripheral nerve or kidney, but also in diabetic pancreas, where progressive decline of islet beta cell mass is the natural history of type 2 diabetes. Use of AR inhibitors, anti-glycation agents and meticulous control of blood glucose are all essential for the prevention of diabetic complications and progressive islet lesions in diabetes. Further elucidation of precise mechanisms of hyperglycemia-induced tissue injury is required for the complete protection of diabetes and its complications.
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