COMPREHENSIVE DNA DIAGNOSTIC SYSTEM FOR SINGLE GENE DISORDERS
| Project/Area Number |
15591080
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | TOHOKU UNIVERSITY |
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Principal Investigator |
KURE Shigeo Tohoku University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (10205221)
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| Co-Investigator(Kenkyū-buntansha) |
OHURA Toshihiro Tohoku University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (10176828)
SUZUKI Youichi Chiba University, Graduate School of Medicine, Professor, 大学院・医学研究院, 教授 (80216457)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Keywords | hyperglycinemia / NMDA glutamate receptor / model mice / inhibitory glycine receptor / abnormal behavior / seizure sencitivity / hyperactivity / increased aggresiveness / グリシン脳症 / NMDA受容体 |
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| Research Abstract |
Nonketotic hyperglycinemia (NKH) is caused by deficiency of the mitochondrial glycine cleavage system, and characterized by accumulation of glycine. Coma and convulsions develop in severe cases while psychomotor retardation and behavioral abnormalities in mild cases. Consequences of glycine accumulation in the central nervous system remain largely unknown. No effective therapy has been established. We identified a GLDC mutation with dominant-negative effect in a patient with NKH. Transgenic expression of the dominant-negative GLDC cDNA generated two mouse lines, which showed significant elevation of glycine level in brain (#10-4 >#5-3). Another transgenic mouse line #wP with depletion of cerebral glycine was also established by expressing normal GLDC. Mice with glycine accumulation showed behavioral abnormalities characteristic to mild NKH, being hyperactive (#10-4), aggressive (#10-4, #5-3), anxious (#10-4 and #5-3), and susceptible to seizures (#10-4, #5-3), as compared with wild type C57BL/6 mice. In sharp contrast, #wP mice showed significant reduction in locomotion, convulsiveness, and anxiety-like activity. Antagonists for the NMDA receptor glycine-binding site, but not an antagonist for the NMDA receptor channel, ameliorated hyperactivity and seizure susceptibility of hyperglycinemic mice. Our results suggest a role of glycine as a behavioral modulator and a novel effective treatment for mild NKH.
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Report
(3 results)
Research Products
(19 results)
