| Project/Area Number |
09671035
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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 |
内分泌・代謝学
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
SHICHIRI Masayoshi Tokyo Medical and Dental University, 医学部, 助手 (10206097)
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| Co-Investigator(Kenkyū-buntansha) |
HIRATA Yukio Tokyo Medical and Dental University, 医学部, 助教授 (50135787)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1998: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | Endothelin-1 / Apoptosis / MAP Kinase / c-Myc / Endothelial cells / Smooth muscle cells / MAPキナーゼ / 線維芽細胞 / ジーン・ターゲティング |
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| Research Abstract |
Vascular smooth muscle cells are known to develop apoptosis following growth factor deprivation. We found that endothelin-1 (ET-1) is an autocrine/paracrine survival factor I from serum deprivation-induced apoptosis for cultured rat endothelial cells. The survival activity of ET- I is mediated via the ETB receptor expressed in endothelial cells.
Overexpression of c-myc gene into cultured fibroblast cells has been reported to elicit massive apoptosis upon serum deprivation, in diploid rat fibroblasts, serum deprivation induced apoptosis following withdrawal of serum, which was antagonized by the addition of low doses of ET-1. The apoptosis observed in the diploid fibroblasts has been demonstrated to be c-myc-dependent, since disruption of one endogenous c-myc gene copy using targeted homologous recombination resulted in marked decrease in serum deprivation-induced apoptosis. In fibroblasts, ET-1 suppressed apoptosis via the ETA receptor through activation of p42/p44 MAP kinase whereas the mechanism behind ETB receptor-mediated endothelial apoptosis remains unclarified. Endothelial cells also underwent apoptosis by the addition of nitric oxide donors and natriuretic peptides, whose effects were also antagonized by ET-1. These observations suggest that apoptosis survival activity of ET-1 in endothelial cells is not restricted to serum deprivation-induced apoptosis. Similar apoptosis survival effect was also elicited by a hypotensive/vasodilatory peptide, adrenomedullin.
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