Novel anti-MCP-1 gene therapy against restenosis and atherosclerosis

针对再狭窄和动脉粥样硬化的新型抗 MCP-1 基因疗法

基本信息

  • 批准号:
    11557056
  • 负责人:
  • 金额:
    $ 8.64万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
  • 财政年份:
    1999
  • 资助国家:
    日本
  • 起止时间:
    1999 至 2001
  • 项目状态:
    已结题

项目摘要

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.
由于再狭窄阻碍了冠状动脉介入治疗的临床益处,因此预防再狭窄是一项重大的临床挑战,这凸显了对基因治疗等新治疗选择的需求。对损伤的炎症反应通过激活包括单核细胞趋化蛋白-1 (MCP-1) 在内的趋化因子加速单核细胞的募集和激活,可能是再狭窄和动脉粥样硬化的核心部分。因此,MCP-1可能是对抗再狭窄和动脉粥样硬化形成的新治疗靶点。我们最近设计了一种抗 MCP-1 基因治疗的新策略,将 MCP-1 基因的 N 末端缺失突变体转染到骨骼肌中。这种突变体 MCP-1 缺乏 N 端氨基酸 2 至 8,称为 7ND,并且作为 MCP-1 的显性失活抑制剂发挥作用。我们已经证明:1) MCP-1 在再狭窄和动脉粥样硬化病变中增加,2) 通过这种策略阻断 MCP-1 可抑制受伤部位的单核细胞浸润/活化,并显着抑制球囊损伤或支架置入后动物颈动脉的再狭窄变化(新内膜增生),以及 3) 阻断 MCP-1 可限制先前存在的动脉粥样硬化的进展 高胆固醇血症小鼠的病变,并将病变成分改善为更稳定的表型(含有更少的巨噬细胞和淋巴细胞,更少的脂质,更多的平滑肌细胞和胶原蛋白)。因此,由MCP-1介导的单核细胞浸润和激活介导的血管炎症在动物再狭窄变化的发展中起着核心作用。因为这种策略似乎是针对人类再狭窄的基因治疗的一种有用形式,所以我们现在正在对接受经皮冠状动脉介入治疗的患者进行这种抗 MCP-1 基因治疗,以减少再狭窄及其并发症。

项目成果

期刊论文数量(54)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Kataoka C, Egashira K, et al.: "Important Role of Rho-kinase in the Pathogenesis of Cardiovascular Inflammation and Remodeling Induced by Long-Term Blockade of Nitric Oxide Synthesis in Rats"Hypertension. 39. 245-250 (2002)
Kataoka C、Egashira K 等人:“Rho 激酶在大鼠长期阻断一氧化氮合成诱导的心血管炎症和重塑发病机制中的重要作用”高血压。
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    0
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Nakamura R, Egashira K, et al.: "Increased Inactivation of Nitric Oxide is Involved in Impaired Coronary Flow Reserve in Does with Tachycardia-Induced Heart Failure"Am J Physiol. 281. H2619-H2625 (2001)
Nakamura R、Egashira K 等人:“一氧化氮失活增加与心动过速引起的心力衰竭患者冠状动脉血流储备受损有关”Am J Physiol。
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    0
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Ni WH, Egashira K, et al.: "Anti-inflammatory and Anti-arteriosclerotic Actions of HMG-CoA Reductase Inhibitors in a Rat Model of Chronic Inhibition of Nitric Oxide Synthesis"Circulation Research. 89. 415-421 (2001)
Ni WH、Egashira K 等人:“HMG-CoA 还原酶抑制剂在慢性抑制一氧化氮合成的大鼠模型中的抗炎和抗动脉硬化作用”循环研究。
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    0
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Koyanagi M,Egashira K, et al: "Role of monocyte chemoattractant protein-1 in cardiovascular remodeling induced by chronic blockade of nitric oxide synthesis in rats."Circulation. 102. 2243-2248 (2000)
Koyanagi M、Egashira K 等人:“单核细胞趋化蛋白-1 在大鼠慢性阻断一氧化氮合成诱导的心血管重塑中的作用。”循环。
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    0
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Zhao Q, Egashira K, et al.: "Vascular Endothelial Growth Factor is Necessary in the Development of Arteriosclerosis by Recruiting/Activating Monocytes in a Rat Model of Long-Term Inhibition of Nitric Oxide Synthesis"Circulation. (印刷中). (2001)
赵 Q、Egashira K 等人:“在长期抑制一氧化氮合成的大鼠模型中,血管内皮生长因子是动脉硬化发展所必需的”(2001 年出版)。 )
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EGASHIRA Kensuke其他文献

EGASHIRA Kensuke的其他文献

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{{ truncateString('EGASHIRA Kensuke', 18)}}的其他基金

the development of novel therapeutic arteriogenesis by nanoparticle-mediated endothelial cell selective delivery system
通过纳米颗粒介导的内皮细胞选择性递送系统开发新型治疗性动脉生成
  • 批准号:
    22390160
  • 财政年份:
    2010
  • 资助金额:
    $ 8.64万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
formulation of bioabsorbable nanoparticle-eluting stent and Mg-Ca alloy stent
生物可吸收纳米颗粒洗脱支架和镁钙合金支架的配方
  • 批准号:
    19390216
  • 财政年份:
    2007
  • 资助金额:
    $ 8.64万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Anti-inflammation therapy targeting monocyte chemoattractant protein-1 as novel strategy to treat cardiovascular disease
针对单核细胞趋化蛋白-1的抗炎治疗作为治疗心血管疾病的新策略
  • 批准号:
    14207036
  • 财政年份:
    2002
  • 资助金额:
    $ 8.64万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
MOLECULAR MECHANISMS OF CARDIOVASCULAR REMODELING INDUCED BY CHRONIC INHIBITION OF NITRIC OXIDE SYNTHESIS : ROLE OF NF-_B AND MCP-1
长期抑制一氧化氮合成诱发心血管重塑的分子机制:NF-_B和MCP-1的作用
  • 批准号:
    11470164
  • 财政年份:
    1999
  • 资助金额:
    $ 8.64万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
molecular mechanisms of vascular remodeling induced by blockade of nitric oxide synthesis
阻断一氧化氮合成诱导血管重塑的分子机制
  • 批准号:
    08457212
  • 财政年份:
    1996
  • 资助金额:
    $ 8.64万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Treatment and prevention of microvascular disorders
微血管疾病的治疗和预防
  • 批准号:
    07557346
  • 财政年份:
    1995
  • 资助金额:
    $ 8.64万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
THE ROLE OF ATP-SENSITIVE POTASSIUM CHANNELS IN THE MECHANISMS OF METABOLIC CORONARY VASODILATION
ATP 敏感钾通道在代谢性冠状血管舒张机制中的作用
  • 批准号:
    06670725
  • 财政年份:
    1994
  • 资助金额:
    $ 8.64万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (C)

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以钙结合蛋白和单核细胞趋化蛋白-1为靶点的肌萎缩侧索硬化症新治疗策略
  • 批准号:
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牙周膜细胞产生的单核细胞趋化蛋白-1 的修复重要性
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    2011
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单核细胞趋化蛋白-1(MCP-1;CCL2)的全身抑制
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    7468646
  • 财政年份:
    2008
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CAPDにおける腹膜劣化抑制:抗Monocyte Chemoattractant Protein-1療法の試み
抑制 CAPD 腹膜恶化:抗单核细胞趋化蛋白 1 疗法的试验
  • 批准号:
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单核细胞趋化蛋白-1 在肥胖及其并发症的发生中的作用。
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    301653-2004
  • 财政年份:
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  • 资助金额:
    $ 8.64万
  • 项目类别:
    Postdoctoral Fellowships
Role of monocyte chemoattractant protein-1 in the development of obesity and its complications.
单核细胞趋化蛋白-1 在肥胖及其并发症的发生中的作用。
  • 批准号:
    301653-2004
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The development of new strategy of heart preservation with. transfection of a dominant-negative inhibitor of monocyte chemoattractant protein-1 gene
心脏保存新策略的制定。
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    14571271
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Anti-inflammation therapy targeting monocyte chemoattractant protein-1 as novel strategy to treat cardiovascular disease
针对单核细胞趋化蛋白-1的抗炎治疗作为治疗心血管疾病的新策略
  • 批准号:
    14207036
  • 财政年份:
    2002
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    $ 8.64万
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    Grant-in-Aid for Scientific Research (A)
Essential role of monocyte chemoattractant protein-1 (MCP1) in development of restenotic changes (neointimal hyperplasia and constrictive remodeling) after balloon angioplasty in hypercholesterolemic rabbits
单核细胞趋化蛋白-1 (MCP1) 在高胆固醇血症兔球囊血管成形术后再狭窄变化(新内膜增生和收缩性重塑)发展中的重要作用
  • 批准号:
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Anti-monocyte Chemoattractant Protein-1 Gene Therapy Prevents Dimethylnitrosamine-induced Hepatic Fibrosis in Rats
抗单核细胞趋化蛋白-1基因治疗预防二甲基亚硝胺诱导的大鼠肝纤维化
  • 批准号:
    12670498
  • 财政年份:
    2000
  • 资助金额:
    $ 8.64万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
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