| Project/Area Number |
11557056
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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 |
Circulatory organs internal medicine
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
EGASHIRA Kensuke Kyushu Univ, Dept of Cardiovasc Med, Associate Prof, 医学部・附属病院, 講師 (60260379)
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| Co-Investigator(Kenkyū-buntansha) |
KOMORI Kimihiro Kyushu Univ, Dept of Surgery, Associate Prof, 大学院・医学研究院, 助教授 (40225587)
SUEISHI Katuo Kyushu Univ, Dept of Cardiovasc Med, Prof, 大学院・医学研究院, 教授 (70108710)
ICHIKI Toshihiro Kyushu Univ, Dept of Cardiovasc Med, Assist Prof, 医学部・附属病院, 助手 (80311843)
NISHIDA Ken-ichi Dai-ichi Pharmaceutical Co., New Product Research Lab, Chief, 創薬研究所, 主任研究員
KAI Hisashi Kurume Univ, Cardiovasc Res Institute, Associate Prof, 循環器病研究所, 助教授 (60281531)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥13,500,000 (Direct Cost: ¥13,500,000)
Fiscal Year 2001: ¥5,400,000 (Direct Cost: ¥5,400,000)
Fiscal Year 2000: ¥5,400,000 (Direct Cost: ¥5,400,000)
Fiscal Year 1999: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Keywords | gene transfer / monocyte chemoattractant protein-1 / restenosis / inflammation / atherosclerosis / 再狭窄 / monocyte chemoattactant protein-1 / 遺伝子治療 / monocyte chemoattractant protein-1 / 一酸化窒素 / ケモカイン / アンジオテンシンII / 血管内皮 |
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| Research Abstract |
Because restenosis hampers clinical benefits of coronary intervention, prevention of restenosis is a major clinical challenge, which highlights the need of new therapeutic options such as gene therapy. Inflammatory responses to injury, which accelerate the recruitment and activation of monocytes through the activation of chemokines including monocyte chemoattractant protein-1 (MCP-1), may be the central part in restenosis and atherosclerosis. Thus, MCP-1 might be a novel therapeutic target against restenosis and atherogenesis. We recently devised a new strategy for anti-MCP-1 gene therapy by transfecting an N-terminal deletion mutant of the MCP-1 gene into skeletal muscles. This mutant MCP-1 lacks the N-terminal amino acid 2 to 8, called 7ND, and works as a dominant-negative inhibitor of MCP-1. We have demonstrate that 1) MCP-1 is increased in restenotic and atherosclerotic lesions, 2) blockade of MCP-1 by this strategy suppressed monocyte infiltration/activation in the injured site and markedly inhibited restenotic changes (neointimal hyperplasia) in the carotid artery of animals after balloon injury or stent placement, and 3) blockade of MCP-1 limited progression of pre-existing atherosclerotic lesions and improved the lesion composition into a more stable phenotype (containing fewer macrophages and lymphocytes, less lipid, more smooth muscle cells and collagen) in hypercholesterolemic mice. Therefore, vascular inflammation mediated by MCP-1-mediated monocyte infiltration and activation plays a central role in the development of restenotic changes in animals. Because this strategy appears to be a useful form of gene therapy against human restenosis, we are now on the way to perform this anti-MCP-1 gene therapy against patients undergoing percutaneous coronary intervention to reduce restenosis and its complications.
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