| Project/Area Number |
13670693
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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 |
Circulatory organs internal medicine
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| Research Institution | The University of Tokyo |
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Principal Investigator |
SHIMOSAWA Tatsuo The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (90231365)
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| Co-Investigator(Kenkyū-buntansha) |
ANDO Katsuyuki The University of Tokyo, Health Care Center, Asistant, 保健センター, 助手 (60184313)
TAKAHASHI Katsutoshi The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (00292863)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2003: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2002: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2001: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | Oxidative stress / Vasoactive substance / Metabolic syndrome / Gene targeting / Organ damage / angiotensin / aging / 血管拡張物質 / 血圧 / インスリン抵抗性 / ノックアウトマウス / 心筋障害 |
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| Research Abstract |
Adrenomedullin (AM) and PAMP are both hypotensive peptide and derived from same precursor but their mechanisms to decrease blood pressure are different. In the present study, we generated AM knockout mice to study its physiological role. Homozygotes are embryonic lethal and thus we used heterozygotes(AM+/-).
Blood pressure is comparable between wild type and AM+/-. When mice are loaded by angiotensin II and salt diet, AM+/-showed remarkable coronary artery damage with higher oxidative stress. It suggests that AM is not only a vasodilator but an endogenous antioxidant (Shimosawa T et al. Circulation, 2002)
Aging is also increases oxidative stress and induces several diseases and thus we investigated aged mice. AM+/-mice showed higher oxidative stress together with insulin resistance in aged mice and the insulin resistance state was reversed by antioxitants or AM treatment. By this study, we revealed that in viva, oxidative stress impairs insulin action and cause metabolic syndrome. Also, hypoxia model, another model of vascular damage were studied in AM+/-and wild mice. We revealed that AM+/-mice shows severer pulmonary artery damage than wild mice and oxidative stress was higher in AM+/-mice (Matsui H. et al. Circulation in press).
In order to study the therapeutical potency of AM, we administered AM locally in cuff injured femoral artery. AM treatment reduced oxidative stress as well as vascular damages. This suggests that AM is a potential antioxidant and can be used to treat oxidative stress-induced organdamages (Kawai J et al. Circulation, 2004).
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