| Project/Area Number |
10218203
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
HIRATA Yukio Tokyo Medical and Dental University, Graduate School, Professor, 大学院・医歯学総合研究科, 教授 (50135787)
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| Co-Investigator(Kenkyū-buntansha) |
SHICHIRI Masayoshi Tokyo Medical and Dental University Hospital, Faculty of Medicine, Assistant Professor, 医学部附属病院, 助教授 (10206097)
今井 泰平 東京医科歯科大学, 医学部附属病院, 助手 (30323679)
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| Project Period (FY) |
1998 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥64,300,000 (Direct Cost: ¥64,300,000)
Fiscal Year 2002: ¥12,600,000 (Direct Cost: ¥12,600,000)
Fiscal Year 2001: ¥12,600,000 (Direct Cost: ¥12,600,000)
Fiscal Year 2000: ¥13,400,000 (Direct Cost: ¥13,400,000)
Fiscal Year 1999: ¥12,600,000 (Direct Cost: ¥12,600,000)
Fiscal Year 1998: ¥13,100,000 (Direct Cost: ¥13,100,000)
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| Keywords | Adrenomedullin / RAMP / CRLR / VSMC / Vascular Remodeling / 細胞遊走 / 血管平滑筋 / 内皮障害 / 内皮 / アポトーシス / c-Myc / Max / 増殖 / チロシンキナーゼ / MAPキナーゼ / 情報伝達 |
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| Research Abstract |
Adrenomedullin (AM) has been shown to function not only as a vasodilator, but also induce a variety of physiological activities, such as cell proliferation, migration and apoptosis. In vascular smooth muscle cell (VSMC), AM stimulates cell increase and growth via MAP Kinase pathway, in which activation of Ca^<2+> - sensitive tyrosine kinase (mol. wt. 120kDa) and recruitment of adaptor proteins (Shc, Grb) lead to ras-dependent MAP kinase activation. The tyrosin kinase has been identified as PYK-2. Thus, AM acts as autocrine/paracrine growth factor for VSMC. On the other hand, AM has been shown to be a potent anti-apoptotic effect on vascular endothelial cells (EC) independently from cAMP. AM potently induces Max gene, thereby antagonizing c-myc-dependent apoptosis as an autocrine/paracrine factor. Furthermore, AM induces chemotactic migration independently from cAMP. RAMP and CRLR comprise AM receptor. The anti-migratory effect on VSMC by AM is mediated via RAMP2/CRLR and /or RAMP3/CRLR, whose effect was lacking in EC and fibroblasts without these receptors. Although AM originally discovered as a vasodilator using cAMP as a second messenger, there may exist several signal transduction pathways independently from cAMP in vascular remodeling, and yet unknown intracellular components essential for AM's action other than RAMP/CRLR. Therefore, elucidation of AM receptor other than RAMP/CRLR and its signal transduction is needed.
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