Development of animal models of human neurodegenerative diseases using transgenic mice
| Project/Area Number |
07558106
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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 |
Neurochemistry/Neuropharmacology
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| Research Institution | Fujita Health University |
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Principal Investigator |
NAGATSU Toshiharu Institute for Comprehensive Medical Science, Fujita Health University, Professor, 総合医科学研究所・神経化学, 教授 (40064802)
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| Co-Investigator(Kenkyū-buntansha) |
NISHII Kazuhiro Institute for Comprehensive Medical Science, Fujita Health University, Researche, 総合医科学研究所・神経化学, 研究員 (50278305)
OHYE Tamae Institute for Comprehensive Medical Science, Fujita Health University, Researche, 総合医科学研究所・神経化学, 研究員 (10247661)
SAWADA Hirohide Institute for Comprehensive Medical Science, Fujita Health University, Researche, 総合医科学研究所・神経化学, 研究員 (30247663)
KOBAYASHI Kazuto Present : Nara Institute of Advanced Science and Technology, Associate Professor, 助教授 (90211903)
水口 智子 藤田保健衛生大学, 総合医科学研究所(神経化学), 研究員 (50247665)
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| Project Period (FY) |
1995 – 1996
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| Project Status |
Completed (Fiscal Year 1996)
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| Budget Amount *help |
¥17,100,000 (Direct Cost: ¥17,100,000)
Fiscal Year 1996: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1995: ¥14,400,000 (Direct Cost: ¥14,400,000)
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| Keywords | transgenic mice / immunotoxin / conditional disruption / neurodegeneration / noradorenergic neurons / autonomic nerve failure / Parkinson's disease / Huntington's disease |
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| Research Abstract |
We development a transgenic approach, termed immunotoxin-mediated cell targeting (IMCT). Transgenic mice were created that express the human interleukin 2 receptor alpha subunit (IL-2Ralpha) in a specific cell type. and the cells were ablated based on the cytotoxicity of a recombinant immunotoxin anti-Tac (Fv) -PE40. DIL transgenic mice were created that express IL-2Ralpha in noradrenergic neurons under the control of the dopamine beta-hydroxylase (DBH) gene promoter. The DIL mice were treated intracerebroventricularly with the immunotoxin, and showed a characteristic behavioral abnormality, accompanied by a loss of DBH-cantaining neurons and a significant decrease in DBH activity and noradrenaline levels in various regions of the brain. When the DIL mice were treated intravenously with the immunotoxin, the sympathetic nerves were degenerated, accompanied by decreases in tissue catecholamine levels, motor activity, body weigh, body temperature, and heart rate, and by abnormal electrocr
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adiogram. The DIL transgenic mice could be the animal models of autonormic nerve failure. The IMCT method was also applied for producing animal models of Parkinson's disease and Huntington's disease. For the animal model of Parkinson's disease, transgenic mice were created that express IL-2Ralpha in dopaminergic neurons in the striatum under the control of the tyrosine hydroxylase (TH) gene promoter. For the animal model of Huntingtons's disease, knockout mice were created that express IL-2Ralpha gene in the locus of dopamine D2 receptor gene by gene targeting. Immunotoxin was injected stereotaxically into the striatum to ablapt either dopamine neurons or GABA neurons. IMCT method was also applied to the negative selection in mouse embryonic stem (ES) cells. By immunotoxin treatment, only ES cells bearing human IL-2Ralpha were efficiently eliminated, indicating that IMCT can be used as a novel strategy for positive and negative selection to enrich ES cell clones with a targeted mutation. Less
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Report
(3 results)
Research Products
(8 results)
