| Project/Area Number |
11557006
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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 | 展開研究 |
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| Research Field |
General pharmacology
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| Research Institution | National Cardiovascular Center Research Institute |
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Principal Investigator |
SAWAMURA Tatsuya National Cardiovascular Center Research Institute, Department of Bioscience, Chief, バイオサイエンス部, 室長 (30243033)
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| Co-Investigator(Kenkyū-buntansha) |
眞崎 知生 国立循環器病センター研究所, 所長 (60009991)
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| Project Period (FY) |
1999 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥13,600,000 (Direct Cost: ¥13,600,000)
Fiscal Year 2002: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2000: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 1999: ¥3,400,000 (Direct Cost: ¥3,400,000)
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| Keywords | oxidized LDL / oxidized LDL receptor / LOX-1 / transgenic mouse / endothelial cells / ノックアウトマウス / 動脈硬化 / 炎症 / レクチン様酸化LDL受容体 / LOX-1リガンド / 内皮細胞 / 血小板 |
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| Research Abstract |
We cloned human LOX-1 gene, and determined its structure and localization at short arm of 12th chromosome. Analyses of expression profile of LOX-1 showed that LOX-1 expression is induced by oxidized LDL, inflammatory cytokines, hypertension, diabetes, and hyperlipidemia.
From the functional aspect, we found that LOX-1 induces generation of superoxide anion and reduction in nitric oxide in endothelial cells, binding oxidized LDL. Activated platelets and leukocytes were found as novel ligands for LOX-1.
To clarify pathological significance of LOX-1, we generated ApoE(-/-)/LOX-1tg mice, which overexpress LOX-1 in the vasculature and muscle in heart, and found that overexpression of LOX-1 accelerates atherosclerosis in coronary artery. In this model accumulation of oxidized LDL and macrophages was also enhanced. We also revealed the involvement of LOX-1 in inflammation, employing models of endotoxin-induced uveites and zymosan-induced arthritis, showing the effectiveness of the treatment with ant-LOX-1 antibody. Furthermore, treatment with anti-LOX-1 antibody siginificantly reduced infarct size in rat model of myocardial infarction. Taken together, LOX-1 is involved in, and anti-LOX-1 therapy would be effective for various disease.
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