Elucidation of C-reactive protein in atherosclerosis and myocardial infarction and translational research

• Project/Area Number: 19390099
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human pathology
• Research Institution: University of Yamanashi
• Principal Investigator: FAN Jianglin University of Yamanashi, 大学院・医学工学総合研究部, 教授 (60272192)
• Co-Investigator(Kenkyū-buntansha): KOIKE Tomonari 山梨大学, 大学院・医学工学総合研究部, 助教 (40432158) ; TEZUKA Hideo 山梨大学, 総合分析実験センター, 准教授 (70155456) ; MORIMOTO Masatoshi 熊本保健科学大学, 保健科学部, 教授 (90136482) ; SHIOMI Masashi 神戸大学, 医学部附属動物実験施設, 准教授 (50226106)
• Project Period (FY): 2007 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2009: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2008: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000); Fiscal Year 2007: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
• Keywords: 動脈硬化 / CRP / 遺伝子改変ウサギ / トランスレーショナル研究 / 冠状動脈硬化 / C-反応蛋白 / 心筋梗塞 / 高脂血症 / 危険因子 / 心血管疾患 / 遺伝子改変動物 / 炎症 / マクロファージ / 動物モデル / トランスジェニック

Research Abstract

我が国の死因30%を占める心筋梗塞や脳卒中といった動脈硬化性疾患の分子病態解明は、国民の健康やQOLを向上させる上で重要な課題である。本研究では心筋梗塞の発症に最も関係している血清炎症マーカーであるC-反応性蛋白の生理機能および動脈硬化の発生における役割について新たに開発した遺伝子改変ウサギモデルにより検討を行った。C-反応性蛋白が動脈硬化の発生を直接に促進することは認められないものの、動脈硬化の進展に有用な診断指標としての意義を明らかにした。また、C-反応性蛋白はバルーン障害により誘導された血栓の形成を促進していることが認められた。

Research Products

• [Journal Article] Expression of human apoAII in transgenic rabbits leads to dyslipidemia: a new model for combined hyperlipidemia. (2009)
  • Author(s): Koike T, Kitajima S, Yu Y, Li Y, Nishijima K, Liu E, Sun H, Waqar AB, Shibata N, Inoue T, Wang Y, Zhang B, Kobayashi J, Morimoto M, Saku K, Watanabe T, Fan J.
  • Journal Title: Arterioscler Thromb Vasc Biol. 29 Pages: 2047-2053
  • Peer Reviewed
• [Journal Article] Human C-reactive protein does not promote atherosclerosis in transgenic rabbits. (2009)
  • Author(s): Koike T, Kitajima S, Yu Y, Nishijima K, Zhang J, Ozaki Y, Morimoto M, Watanabe T, Bhakdi S, Asada Y, Chen YE, Fan J.
  • Journal Title: Circulation 120 Pages: 2088-2094
  • Peer Reviewed
• [Journal Article] Endotoxin accelerates atherosclerosis independent of complement activation. (2009)
  • Author(s): Reifenberg K, Lehr HA, Fan J, Koike T, Wiese E, Kupper I, Sagban TA, Schaefer SC, Zahringer U, Torzewski M, Lackner KJ, Bhakdi S.
  • Journal Title: Thromb Res. 123 Pages: 653-658
  • Peer Reviewed
• [Journal Article] Expression of human apoAII in transgenic rabbits leads to dyslipidemia : a new model for combined hyperlipidemia. (2009)
  • Author(s): Koike T, et al.
  • Journal Title: Arterioscler Thromb Vase Biol. 29 Pages: 2047-2053
  • Peer Reviewed
• [Journal Article] Human C-reactive protein does not promote atherosclerosis in transgenic rabbits. (2009)
  • Author(s): Koike T, et al.
  • Journal Title: Circulation 120 Pages: 2088-2094
  • Peer Reviewed
• [Journal Article] Endotoxin accelerates atherosclerosis independent of complement activation. (2009)
  • Author(s): Reifenberg K, et al.
  • Journal Title: Thromb Res. 123 Pages: 653-658
  • Peer Reviewed
• [Journal Article] Endotoxin accelerates atherosclerosis independent of complement activation (2009)
  • Author(s): Reifenberg K, Lehr HA, Fan J, Koike T, Wiese E, Kupper I, Sagban TA, Schaefer SC, Zahringer U, Torzewski M, Lackner KJ, Bhakdi S
  • Journal Title: Thromb Res 123 Pages: 653-658
  • Peer Reviewed
• [Journal Article] The effects of rosiglitazone on aortic atherosclerosis of cholesterol-fed rabbits. (2008)
  • Author(s): Zhao S, Zhang C, Lin Y, Yang P, Yu Q, Chu Y, Yang P, Fan J, Liu E.
  • Journal Title: Thromb Res. 123 Pages: 281-287
  • Peer Reviewed
• [Journal Article] Matrix metalloproteinase 12 accelerates the initiation of atherosclerosis and stimulates the progression of fatty streaks to fibrous plaques in transgenic rabbits. (2008)
  • Author(s): Yamada S, Wang KY, Tanimoto A, Fan J, Shimajiri S, Kitajima S, Morimoto M, Tsutsui M, Watanabe T, Yasumoto K, Sasaguri Y.
  • Journal Title: Am J Pathol. 172 Pages: 1419-1429
  • Peer Reviewed
• [Journal Article] Spontaneous atherosclerosis in aged lipoprotein lipase-deficient mice with severe hypertriglyceridemia on a normal chow diet. (2008)
  • Author(s): Zhang X, Qi R, Xian X, Yang F, Blackstein M, Deng X, Fan J, Ross C, Karasinska J, Hayden MR, Liu G.
  • Journal Title: Circ Res. 102 Pages: 250-256
  • Peer Reviewed
• [Journal Article] Unstable coronary plaques and cardiac events in myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits: questions and quandaries. (2008)
  • Author(s): Shiomi M, Fan J.
  • Journal Title: Curr Opin Lipidol. 19 Pages: 631-636
  • Peer Reviewed
• [Journal Article] Unstable coronary plaques and cardiac events in myocardialinfarction-prone Watanabe heritable hyperlipidemic rabbits : questionsand quandaries (2008)
  • Author(s): Shiomi M, Fan J
  • Journal Title: Curr Opin Lipidol 19 Pages: 631-636
  • Peer Reviewed
• [Journal Article] Matrix metalloproteinase 12 accelerates the initiation of atherosclerosis and stimulates the progression of fatty streaks to fibrous plaques in transgenic rabbits (2008)
  • Author(s): Yamada S, Wang KY, Tanimoto A, Fan J, Shimajiri S, Kitajima s, Morimoto M, Tsutsui M, Watanabe T, Yasumoto K, Sasaguri Y
  • Journal Title: Am J Pathol 172 Pages: 1419-1429
  • Peer Reviewed
• [Journal Article] Coronary plaque rupture and acute coronary syndrome, (2008)
  • Author(s): Shiomi M, Fan J
  • Journal Title: Curr Opin Lipidol (In press)
  • Peer Reviewed
• [Journal Article] Spontaneous atherosclerosis in aged lipoprotein lipase-deficient mice with severe hypertriglyceridemia on a normal chow diet (2008)
  • Author(s): Zhang X, et. al.
  • Journal Title: Circ Res 102 Pages: 250-256
  • Peer Reviewed
• [Journal Article] Diet-induced central obesity and insulin resistance in rabbits, (2008)
  • Author(s): Zhao S, et. al.
  • Journal Title: J Anim Physiol Anim Nutr(Berl) 92 Pages: 105-111
  • Peer Reviewed
• [Journal Article] Expression of LPL in endothelial-intact artery results in lipid deposition and vascular cell adhesion molecule-1 upregulation in both LPL and ApoE-deficient mice. (2007)
  • Author(s): Wang J, Xian X, Huang W, Chen L, Wu L, Zhu Y, Fan J, Ross C, Hayden MR, Liu G.
  • Journal Title: Arterioscler Thromb Vasc Biol. 27 Pages: 197-203
  • Peer Reviewed
• [Journal Article] Increased expression of vascular endothelial growth factor in kidney leads to progressive impairment of glomerular functions. (2007)
  • Author(s): Liu E, Morimoto M, Kitajima S, Koike T, Yu Y, Shiiki H, Nagata M, Watanabe T, Fan J.
  • Journal Title: J Am Soc Nephrol. 18 Pages: 2094-2104
  • Peer Reviewed
• [Journal Article] Lp(a) enhances coronary atherosclerosis in transgenic Watanabe heritable hyperlipidemic rabbits. (2007)
  • Author(s): Kitajima S, Jin Y, Koike T, Yu Y, Liu E, Shiomi M, Marcovina SM, Morimoto M, Watanabe T, Fan J.
  • Journal Title: Atherosclerosis. 193 Pages: 269-276
  • Peer Reviewed
• [Journal Article] Increased expression of vascular endothelial growth factor in kidney leads to progressive impairment of glomerular functions (2007)
  • Author(s): Liu, E, et. al.
  • Journal Title: J Am Soc Nephrol 18 Pages: 2094-2104
  • Peer Reviewed
• [Journal Article] Expression of LPL in endothelial-intact artery results in lipid deposition and vascular cell adhesion molecule-1 upregulation in both LPL and ApoE-deficient mice (2007)
  • Author(s): Wang J, et. al.
  • Journal Title: Arterioscler Thromb Vasc Biol 27 Pages: 197-203
  • Peer Reviewed
• [Journal Article] Lp(a)enhances coronary atherosclerosis in transgenic Watanabe heritable hyperlipidemic rabbits (2007)
  • Author(s): Kitajima S, et. al.
  • Journal Title: Atherosclerosis 193 Pages: 269-276
  • Peer Reviewed
• [Journal Article] Re-establishment of complement C6-deficient rabbit colony by cryopreserved sperm transported from abroad (2007)
  • Author(s): Liu, E, et. al.
  • Journal Title: Exp Anim 56 Pages: 167-171
  • Peer Reviewed
• [Journal Article] Increased expression of human macrophage metalloelastase(MMP-12)is associated with the invasion of endometrial adenocarcinoma (2007)
  • Author(s): Yang, X, et. al.
  • Journal Title: Pathol Res Pract 203 Pages: 499-505
  • Peer Reviewed
• [Presentation] Transgenic rabbits for translational research (2009)
  • Author(s): 範江林
  • Organizer: 遺伝子改変ウサギ国際シンポジウム
  • Place of Presentation: 中国西安市
  • Year and Date: 2009-06-04
• [Presentation] 動脈硬化の研究のための新たな遺伝子改変ウサギ・モデルの開発と応用. (2008)
  • Author(s): 範江林
  • Organizer: 第40回日本動脈硬化学会総会・学術集会
  • Place of Presentation: つくば国際会議場
  • Year and Date: 2008-07-11
• [Presentation] 動脈硬化の発症におけるCRPの役割 : Marker or Maker? (2008)
  • Author(s): 範江林, 小池智也, 柴田信光
  • Organizer: 第97回日本病理学会総会
  • Place of Presentation: 石川県金沢市(石川県立音楽堂、ホテル日航金沢等)
  • Year and Date: 2008-05-15
• [Presentation] Transgenic Rabbits for Translational Research (2007)
  • Author(s): 範 江林
  • Organizer: 関西実験動物研究会 第95回研究会
  • Place of Presentation: 神戸市中央区(神戸大学医学部)
  • Year and Date: 2007-09-14
• [Presentation] 遺伝子改変ウサギ・モデルによるトランスレーショナルリサーチへの展開 (2007)
  • Author(s): 範 江林
  • Organizer: 第24回日本疾患モデル学会総会
  • Place of Presentation: つくば市(つくば国際会議場)
  • Year and Date: 2007-09-01
• [Presentation] CRP in atherosclerosis its origin and pathophysiological significance (2007)
  • Author(s): 範 江林
  • Organizer: Cardiovascular Summer Lecture 2007
  • Place of Presentation: 東京都文京区(東京ガーデンパレス)
  • Year and Date: 2007-08-23
• [Presentation] 動脈硬化の形成におけるC反応性蛋白の役割 (2007)
  • Author(s): 範 江林
  • Organizer: 第28回日本炎症・再生医学会
  • Place of Presentation: 東京都新宿区(京王プラザホテル)
  • Year and Date: 2007-08-02
• [Presentation] 動脈硬化の発生・進展におけるCRPの役割:Marker or Maker or both? (2007)
  • Author(s): 範江林
  • Organizer: 第8回ABカンファレンス
  • Place of Presentation: 神戸ポートピアホテル
  • Year and Date: 2007-07-28
• [Presentation] 動脈硬化の発生・進展におけるCRPの役割 (2007)
  • Author(s): 範 江林
  • Organizer: 第8回ABカンファレンス
  • Place of Presentation: 神戸市中央区(神戸ポートピアホテル本館)
  • Year and Date: 2007-07-28
• [Presentation] Transgenic Rabbit Models for the Study of Atherosclerosis. (2007)
  • Author(s): 範 江林
  • Organizer: Sweden(AstraZeneca R&D Molndal Sweden)
  • Place of Presentation: Sweden(Astra Zeneca R&D Molndal Sweden)
  • Year and Date: 2007-06-26
• [Book] Rabbit genomics, transgenesis, cloning and models: Springer(Rabbit Biotechnology) (2009)
  • Author(s): Houdebine L, Fan J.
  • Total Pages: 136
• [Book] Rabbit Biotechnology : Rabbit genomics, transgenesis, cloning and models : (2009)
  • Author(s): Fan J, et al.
  • Total Pages: 140
  • Publisher: Springer
• [Book] Rabbit Biotechnology (2009)
  • Author(s): Houdebine, ML, Fan, J
  • Total Pages: 140
  • Publisher: Springer
• [Remarks] ホームページ等
  • URL: http://www.med.yamanashi.ac.jp/clinical_basic/pathol01/
• [Remarks]
  • URL: http://www.med.yamanashi.ac.jp/clinical_basic/patho101/
• [Remarks]
  • URL: http://www.med.yamanashi.ac.jp/clinical_basic/pathol01/
• [Remarks]
  • URL: http://www.med.yamanashi.ac.jp/clinical_basic/patho101/
• [Patent(Industrial Property Rights)] ヒトC反応性蛋白遺伝子導入ウサギ (2009)
  • Inventor(s): 国立大学法人山梨大学、国立大学法人佐賀大学、MOREHOUSE COLLEGE
  • Industrial Property Rights Holder: 範江林, 他
  • Industrial Property Number: 2009-141742
  • Filing Date: 2009-06-15
  • Acquisition Date: 2009-06-15
• [Patent(Industrial Property Rights)] ヒトC反応性蛋白遺伝子導入ウサギ (2007)
  • Inventor(s): 北嶋修司, 範 江林
  • Industrial Property Rights Holder: 佐賀大学, 山梨大学
  • Filing Date: 2007
  • Overseas