| Project/Area Number |
06454693
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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 |
Nerve anatomy/Neuropathology
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
ITOHARA Shigeyoshi Kyoto University, Institute for Virus Research, Associate Professor, ウイルス研究所, 助教授 (60252524)
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| Co-Investigator(Kenkyū-buntansha) |
IKEDA Toshio Kyoto University, Institute for Virus Research, Instructor, ウイルス研究所, 助手 (80252526)
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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 |
¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 1996: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1995: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1994: ¥3,100,000 (Direct Cost: ¥3,100,000)
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| Keywords | Gelatinase A / Matrix Metalloproteinase 2 / Knockout mouse / Amyloid Precursor Protein / Secretase / Growth and Metastasis of tumor cells / Protease / Metalloproteinase / Alzheimer's disease / Amyloid precursor protein / Secretase / Secretion / Gene targeting / Mutant mouse / ゲラチナーゼ / アルツハイマー / アミロイド蛋白質 |
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| Research Abstract |
Gelatinase A belongs to a family of mammalian metalloproteinases that are able to degrade a number of matrix proteins. The gelatinase A is synthesized as pro-enzyme, and removing amino-terminal 'pro' domain by protease(s) convert it to permanently active, mature form of the enzyme. Because of its substrate specificity and tissue distribution, it has been predicted that the enzymes play an important role in remodeling of tissue architecture. Gelatinase A may also play a role in the metastasis and growth of malignant tumors. Interestingly, it has been suggested that gelatinase A may act on amyloid precursor protein (APP) either as alpha-secretase or as beta-secretase. On the other hand, it was found that all isoforms of secreted APP have in the c-terminal region a domain that inhibits gelatinase A activity. These results suggested a role of gelatinase A on the metabolism of APP.
To clarify these putative roles of this enzyme, we generated gelatinase A knockout mice. The mutant mice developed normally, except for slightly slower growth rate as compared to that of wildtype mice, and were fertile. Although gelatinase A is expressed ubiquitously, and has been thought to be important for the remodeling of tissue architecture during development, the mutant mice did not show any gross anatomical abnormalities. We observed normal secretion and metabolic kinetics of APP in the tissues and cultured fibroblasts from mutant mice. Thus, we concluded that the gelatinase A (MMP-2) is neither the major alpha-nor beta-secretases. Preliminary results might support the idea that the enzyme plays a role on tumor growth.
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