2002 Fiscal Year Final Research Report Summary
The study of the mechanism of cataract formation using aminoguanidine, which has the ability to prevent lens opacification.
| Project/Area Number |
12670150
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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 |
Pathological medical chemistry
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| Research Institution | Tokyo Metropolitan Institute of Gerontology |
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Principal Investigator |
INOMATA Mitsushi Tokyo Metropolitan Institute of Gerontology, Biomembrane Research Group, Senior Research Scientist, 東京都老人総合研究所, 主任研究員 (30142649)
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| Project Period (FY) |
2000 – 2002
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| Keywords | cataract / aminoguanidine / inducible nitric oxide synthase / calpain / calcium ion / proteolysis / crystallin |
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| Research Abstract |
The Shumiya cataract rat (SCR) is a hereditary cataract model in which lens opacity appears spontaneously in the nuclear and perinuclear portions at 11-12 weeks of age. We found incidentally that the oral administration of aminoguanidine (AG) strongly inhibits the development of lens opacification in SCR. Since our previous results suggested that calpain-mediated proteolysis contributes to lens opacification during cataract formation, we examined the calpain-mediated proteolysis in AG-treated SCR lenses. The results showed that the calpain-mediated limited proteolysis of crystallins is inhibited by AG-treatment. However, the administration of AG had no effect on the substrate susceptibility to calpain. On the other hand, the autolytic activation of calpain in AG-treated lenses was inhibited, although AG itself did not inhibit calpain activity in vitro. Then, we analyzed the effect of AG-treatment on calcium concentrations in lens, and found that the elevation in calcium concentration t
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hat should occur prior to cataractogenesis in lenses is strongly suppressed by AG-treatment. Since AG is an inhibitor of inducible nitric oxide synthase (iNOS), it is of interest and significance to confirm whether iNOS is highly expressed in cataractous lenses. Therefore, we examined whether iNOS is upregulated and involved in cataract formation. High levels of iNOS mRNA and iNOS protein were expressed in cataractous lenses compared with normal lenses. The increase in their expressions was markedly suppressed by the oral administration of AG, which acts to prevent lens opacification. The induction of iNOS protein was observed before the elevation of calcium content and the acceleration of calpain-mediated proteolysis, both of which are closely related to the development of lens opacification. These findings strongly suggest that iNOS is involved in cataract formation in SCR. It is conceivable that upregulation of iNOS causes the calcium influx into lens cells and subsequent activation of calpain. Less
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Research Products
(11 results)
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[Publications] Inomata, M., Hayashi, M., Ito, Y., Matsubara, Y., Takehana, M., Kawashima, S. and Shumiya, S.: "Comparison of Lp82- and m-calpain-medialed proteolysis during cataractogenesis in Shumiya cataract rat (SCR)"Curr. Eye Res.. 25. 207-213 (2002)
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「研究成果報告書概要(欧文)」より
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[Publications] Manya, H., Inomata, M., Fujimori, T., Dohmae, N., Sato, Y., Takio, K., Nabeshima, YI and Endo, T.: "Klotho protein deficiency leads to overactivation of μ-calpain"J. Biol. Chem.. 277. 35503-35508 (2002)
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[Publications] Waheed, A.A., Shimada, Y., Heijnen, H.F., Nakamura, M., Inomata. M., Hayashi, M., Iwashita, S., Slot, J.W. and Ohno-Iwashita, Y.: "Selective binding of perfringolysin O derivative to cholesterol-rich membrane microdomains (rafts)"Proc Natl Acad Sci U S A.. 98. 4926-4931 (2001)
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「研究成果報告書概要(欧文)」より
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