2000 Fiscal Year Annual Research Report

血管より産生される新たな分泌タンパクの生理活性解明とその臨床応用法の開発

Research Project

Project/Area Number	11557052
Research Institution	KYOTO UNIVERSITY
Principal Investigator	篠山重威京都大学, 医学研究科, 教授 (70109007)
Co-Investigator(Kenkyū-buntansha)	田代啓京都大学, 遺伝子実験施設, 助教授 (10263097) 松森昭京都大学, 医学研究科, 助教授 (70135573)
Keywords	動脈硬化 / PTCA / 再狭窄 / 血管内皮細胞 / 血管平滑筋細胞 / 神経提細胞 / 発生 / インテグリン
Research Abstract	マウス胎児心臓からシグナル・シークエンス・トラップ法にてクローニングした新規分泌蛋白の一つであるDANCEはカルシウム結合性EGFドメインを6個有し、RGD配列を介してインテグリンと結合することが示された。FISH法にてヒト第14染色体長腕q32.1にあることを突き止めたが、現在のところ同部位に遺伝的疾患は報告されていない。更なる機能解析として正常・病的動物での発現解析を進めた。マウス胎児においては胎生9.5日になり移動中の神経提細胞とそれに由来する鰓弓間葉細胞及び心外膜に発現を認める。胎生12.5日では心流出路と大動脈(内皮・平滑筋細胞の両者)で発現が強いが、心内膜床や頭部・体節間などの間葉組織でも発現を認める。胎生14.5日になると、神経提由来組織での発現が変化し、頭部間葉・心流出路・交惑神経節で発現が持続する一方、副腎などでは発現が消失する。成体では大動脈での発現も低下するが、胸部大動脈肋間枝分岐部では局所的に強い発現を認める。これは血行動態的なストレスから動脈硬化を起こしやすい解剖学的部位と一致するため、高コレステロール食投与LDL受容体欠損マウスで調べたところ、プラーク病変を覆う内皮細胞での有意な発現増強が判明、動脈硬化病変でのDANCEの関わりが示唆された。またラット頸動脈バルーン傷害モデルでは傷害後発現が亢進し14日後に最大となった。詳細な検討では剥離後再生した内皮及び平滑筋細胞で発現するが、分裂増殖の活発な場所から少し離れた休止期に入った領域で特に強い発現を認めた。以上よりDANOEは血管病変における病的増殖細胞に増殖抑制のシグナルを伝える作用が示唆され、経皮的冠動脈形成術後の再狭窄予防などの臨床応用への発展の可能性も秘めた蛋白であることが判明した。遺伝子欠損マウスの作成にも成功、異常な表現型の存在を確認しており、現在そのメカニズムの解明を行っている。

Research Products

(19 results)

All Other

All Publications (19 results)

[Publications] Matsumori A, et al.: "Amlodipine inhibits the production of cytokine induced by ouabain. Amlodipine inhibits the production of cytokine induced by ouabain."Cytokine. 12. 294-297 (2000)
[Publications] Matsumori A, et al.: "Hepatitis C virus and cardiomyopathy."Herz. 25. 249-254 (2000)
[Publications] Kakio T, et al.: "Roles and relationship of macrophages and monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 in the ischemic and reperfused rat heart."Lab Invest. 80. 1121-1126 (2000)
[Publications] Matsumori A, et al.: "Hepatitis C virus from the hearts of patients with myocarditis and cardiomyopathy."Lab Invest. 80. 1137-1142 (2000)
[Publications] Naruse TK, et al.: "HLA-DQB1^*0601 is primarily associated with the susceptibility to cardiac sarcoidosis."Tissue Antigens. 56. 52-57 (2000)
[Publications] Nakamura K, et al.: "Hepatitis C virus infection in a patient with dermatomyositis and left ventricular dysfunction."Jpn Circ J. 64. 623-626 (2000)
[Publications] Matsumori A, et al.: "Hypertrophic cardiomyopathy as a manifestation of cardiac sarcoidosis."Jpn Circ J. 64. 679-683 (2000)
[Publications] Matsumori A, et al.: "Circulating hepatocyte growth factor as a marker of thrombus formation in unstable angina pectoris."Jpn Circ J. 64. 805-807 (2000)
[Publications] Matsumori A, et al.: "Pimobendan inhibits the activation of transcription factor NF-κB.A mechanism which explains its inhibition of cytokine production and inducible nitric oxide synthase."Life Sci. 67. 2513-2519 (2000)
[Publications] Matsumori A, et al.: "Nifedipine inhibits of transcription factor NF-κB."Life Sci. 67. 2655-2561 (2000)
[Publications] Tadamura E, et al.: "Significant regional heterogeneity of coronary flow reserve in paediatric hypertrophic cardiomyopathy."Eur J Nucl Med. 27. 1340-1348 (2000)
[Publications] Arimura T, et al.: "Characterization of human nebulette gene : A polymorphism in an actin-binding morif is associated with non-familial dilated cardiomyopathy."Human Genetics. 107. 440-451 (2000)
[Publications] Ohashi N, et al.: "Role of p38 mitogen-activated protein kinase in neointimal hyperplasia after vascular injury."Arterioscler Thromb Vasc Biol. 20. 2521-2526 (2000)
[Publications] Nishimura H, et al.: "Autoimmune dilated cardiomyopathy in PD-1 receptor deficient mice."Science. 291. 391-322 (2001)
[Publications] Matsumori A.: "The role of inflammatory mediators in the failing heart : Immunomodulation of cytokines in experimental models of heart failure."Heart Failure Reviews. 6. 129-136 (2001)
[Publications] Sato Y, et al.: "Persistently increased serum concentrations of cardiac troponin T in patients with idiopathic dilated cardiomyopathy are predictive of adverse outcomes."Circulation. 103. 369-374 (2001)
[Publications] Matsumori A.: "Insights into the pathophysiology of heart failure based on a new concept."Asian Medical Journal. 44. 36-41 (2001)
[Publications] Matsumori A.: "1.3 Cytokines and heart failure : Pathophysiological roles and therapeutic implications."Heart Failure Frontiers in Cardiology ed.by A.Kitabatake,S.Sasayama,G.S.Francis, Springer. 11 (2000)
[Publications] Matsumori A.: "Hepatitis C virus infection in hypertrophic or dilated cardiomyopathy"The Hypertrophied heart N.Takeda,M.Nagano and N.S.Dhalla (eds).Kluwer Academic. 9 (2000)

2000 Fiscal Year Annual Research Report

血管より産生される新たな分泌タンパクの生理活性解明とその臨床応用法の開発

Principal Investigator

篠山 重威 京都大学, 医学研究科, 教授 (70109007)

Research Products

[Publications] Matsumori A, et al.: "Amlodipine inhibits the production of cytokine induced by ouabain. Amlodipine inhibits the production of cytokine induced by ouabain."Cytokine. 12. 294-297 (2000)

[Publications] Matsumori A, et al.: "Hepatitis C virus and cardiomyopathy."Herz. 25. 249-254 (2000)

[Publications] Kakio T, et al.: "Roles and relationship of macrophages and monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 in the ischemic and reperfused rat heart."Lab Invest. 80. 1121-1126 (2000)

[Publications] Matsumori A, et al.: "Hepatitis C virus from the hearts of patients with myocarditis and cardiomyopathy."Lab Invest. 80. 1137-1142 (2000)

[Publications] Naruse TK, et al.: "HLA-DQB1^*0601 is primarily associated with the susceptibility to cardiac sarcoidosis."Tissue Antigens. 56. 52-57 (2000)

[Publications] Nakamura K, et al.: "Hepatitis C virus infection in a patient with dermatomyositis and left ventricular dysfunction."Jpn Circ J. 64. 623-626 (2000)

[Publications] Matsumori A, et al.: "Hypertrophic cardiomyopathy as a manifestation of cardiac sarcoidosis."Jpn Circ J. 64. 679-683 (2000)

[Publications] Matsumori A, et al.: "Circulating hepatocyte growth factor as a marker of thrombus formation in unstable angina pectoris."Jpn Circ J. 64. 805-807 (2000)

[Publications] Matsumori A, et al.: "Pimobendan inhibits the activation of transcription factor NF-κB.A mechanism which explains its inhibition of cytokine production and inducible nitric oxide synthase."Life Sci. 67. 2513-2519 (2000)

[Publications] Matsumori A, et al.: "Nifedipine inhibits of transcription factor NF-κB."Life Sci. 67. 2655-2561 (2000)

[Publications] Tadamura E, et al.: "Significant regional heterogeneity of coronary flow reserve in paediatric hypertrophic cardiomyopathy."Eur J Nucl Med. 27. 1340-1348 (2000)

[Publications] Arimura T, et al.: "Characterization of human nebulette gene : A polymorphism in an actin-binding morif is associated with non-familial dilated cardiomyopathy."Human Genetics. 107. 440-451 (2000)

[Publications] Ohashi N, et al.: "Role of p38 mitogen-activated protein kinase in neointimal hyperplasia after vascular injury."Arterioscler Thromb Vasc Biol. 20. 2521-2526 (2000)

[Publications] Nishimura H, et al.: "Autoimmune dilated cardiomyopathy in PD-1 receptor deficient mice."Science. 291. 391-322 (2001)

[Publications] Matsumori A.: "The role of inflammatory mediators in the failing heart : Immunomodulation of cytokines in experimental models of heart failure."Heart Failure Reviews. 6. 129-136 (2001)

[Publications] Sato Y, et al.: "Persistently increased serum concentrations of cardiac troponin T in patients with idiopathic dilated cardiomyopathy are predictive of adverse outcomes."Circulation. 103. 369-374 (2001)

[Publications] Matsumori A.: "Insights into the pathophysiology of heart failure based on a new concept."Asian Medical Journal. 44. 36-41 (2001)

[Publications] Matsumori A.: "1.3 Cytokines and heart failure : Pathophysiological roles and therapeutic implications."Heart Failure Frontiers in Cardiology ed.by A.Kitabatake,S.Sasayama,G.S.Francis, Springer. 11 (2000)

[Publications] Matsumori A.: "Hepatitis C virus infection in hypertrophic or dilated cardiomyopathy"The Hypertrophied heart N.Takeda,M.Nagano and N.S.Dhalla (eds).Kluwer Academic. 9 (2000)

篠山重威京都大学, 医学研究科, 教授 (70109007)