1997 年度実績報告書

動脈硬化症を中心とした心血管系における遺伝子治療法の開発

研究課題

研究課題/領域番号	08044273
研究機関	京都大学
研究代表者	篠山重威京都大学, 医学研究科, 教授 (70109007)
研究分担者	ゴールドシュタインジョテキサス大学, 医学部, 教授ジェラルドロバートカソリード大学, 遺伝子導入・治療センター, 教授長谷川浩二京都大学, 医学研究科, 助手 (50283594) 松森昭京都大学, 医学研究科, 講師 (70135573)
キーワード	アデノウイルス / 遺伝子導入 / 遺伝子治療 / ポリリジン修飾アデノウイルス / 心血管系 / サイトカイン / 増殖因子 / イオンチャネル
研究概要	アデノウイルスによる心血管系における遺伝子導入および遺伝子治療の技術確立のために共同研究が行われた。研究代表者のグループでは、in vivo,in vitroモデルの確立と循環器疾患に関与する重要な遺伝子の構造、機能、発現制御の検討が行われた。ラットなどの心筋細胞、ヒト由来を含む内皮細胞、平滑筋細胞の初代培養系が遺伝子導入のターゲット細胞として確立された。in vivoモデルとしては、冠動脈結紮による心筋虚血、心筋梗塞モデル、マウス心移植モデル、ウイルス性心筋炎モデル、心筋症モデル、心不全モデルが確立された。そしてこれらの病態モデルがヒト疾患モデルとして十分有用であることが証明された。重要な遺伝子としてサイトカイン、増殖因子、イオンチャネル、転写調節因子の種々の病態における発現調節、機能解析がおこなわれた。これには、サイトカインの各種心疾患での発現調節とそのmodulationによる病態に対する影響の証明、種々の増殖因子による血管新生に対する影響、イオンチャネル異常による不整脈発症機序の解明、転写調節因子と心肥大の関係などが明らかにされた。海外の研究協力者により平行してアデノウイルスの作成、培養系、モデル動物系においての遺伝子導入についての検討が行われた。これには、プラスミノーゲンアクティベータ-遺伝子の導入による凝固系の調節、エンドセリン前駆体導入による高血圧症の発症、NO合成酵素の導入による肺血管収縮の影響などが検討された。また、ポリリジン修飾ウイルスによる各種心血管系培養細胞への遺伝子導入が検討されレポーター遺伝子が良好に導入されることが確認された。このベクターは、ウイルスが不活化されているためbiohazardとしての安全性が高いと予想されること、導入遺伝子のサイズの制限を受けないことなどが利点として考えられるため引き続きモデル動物への遺伝子導入とその有用性の検討が行われる予定である。また、研究代表者側で検討された種々の遺伝子およびその突然変異体などのアデノウイルス組み換え体などを共同研究者と作成し、モデル動物へ導入することでその病態生理の解明が進むと考えられる。今回の共同研究により、心血管系においていかなる遺伝子が重要な役割を果たしているか、そしてアデノウイルスベクターを用いた遺伝子導入が非常に強力な病態生理解明の糸口となることがすでに種々の系で確認された。また、これらの過程で海外共同研究者との密接な討議、研究成果の交換により、最新の情報を交換でき、また将来の研究発展の基盤となり成果の多い共同研究となった。

研究成果

(36件)

すべてその他

すべて文献書誌 (36件)

[文献書誌] Furukawa Y, et al.: "Angiotensin II receptor antagonist TCV-116 reduces gerft coronary artery disease and preserves graft status in a murine model." Circulation. 93. 333-339 (1996)
[文献書誌] Sasayama S, et al.: "Role of cytokines in the syndrome of heart failure." Int Med. 35. 60-63 (1996)
[文献書誌] Matsumori A, et al.: "Increased circulating hepatocyte growth factor in the early stage of acute myocardial infarction" Biochem Biophys Res Commun. 221. 391-395 (1996)
[文献書誌] Furukawa Y, et al.: "Immunomodulation by an adenylate cyclase activator,NKH477,in vivo and in vitro." Clin Immunol Immunopathol. 79. 25-35 (1996)
[文献書誌] Hasegawa K, et al.: "Endothelin-1 and its receptor in hypertrophic cardiomyopathy." Hypertension. 27. 254-264 (1996)
[文献書誌] Matsumori A, et al.: "Detection of hepatitis C virus RNA from the heart of patients with hypertrophic cardiomyopathy." Biochem Biophys Res Commun. 222. 678-682 (1996)
[文献書誌] Matsumori A.: "Cytokines in myocarditis and cardiomyopathies." Curr Opin Cardiol. 11. 302-309 (1996)
[文献書誌] Matsumori A, et al.: "Antimyosin antibody imaging in clinical myocarditis and cardiomyopathy:principle and application." Int J Cardiol. 54. 183-190 (1996)
[文献書誌] Matsumori A, et al.: "Inotropic agents differentially inhibit the induction of nitric oxide synthase by endotoxin in cultured macrophages." Life Sci. 59. PL121-PL125 (1996)
[文献書誌] LiL-X, et al.: "Comparative study of 201TI-scintigraphic image and myocardial pathologic findings in patients with dilated cardiomyopathy." Nucl Med. 10. 307-314 (1996)
[文献書誌] Nakamura H, et al.: "A pathogenic mechanisms of chronic ongoing myocarditis." Jpn Circ J. 60. 609-617 (1996)
[文献書誌] Matsumori A, et al.: "Differential modulation of cytokine production by drugs:Implication for therapy in heart failure." J Mol Cell Cardiol. 28. 2491-2499 (1996)
[文献書誌] Sasayama S, et al.: "Vesnarinone:A Potential Cytokine Inhibitor." J Cardiac Failure. 2. 251-258 (1996)
[文献書誌] Shioi T, et al.: "Persistent expression of cytokine in the chronic stage of viral myocarditis in mice." Circulation. 94. 2930-2937 (1996)
[文献書誌] Matsumori A, et al.: "Newer aspects of pathogenesis of heart failure:Hepatitis C virus infection in myocarditis and cardiomyopathy." J Cardiac Failure. 2. S187-S194 (1996)
[文献書誌] Sasayama S, et al.: "Immunomodulation:A new horizon for medical treatment of heart failure." J Cardiac Failure. 2. S287-S294 (1996)
[文献書誌] Tadamura E, et al.: "Myocardial metabolic changes in hypertrophic cardiomyopathy." J Nucl Med. 37. 572-577 (1996)
[文献書誌] Nakamura H, et al.: "Autoimmune respones in chronic ongoing myocarditis demonstrated by heterotopic cardiac transplantation in mice." Circulation. 94. 3348-3354 (1996)
[文献書誌] Matsumori A.: "Molecular and immune mechanisms in the pathogenesis of cardiomyopathy." Jpn Circ J. 61. 275-291 (1997)
[文献書誌] Ono K, et al.: "Enhanced expression of hepatocyte growth factor/c-met by myocardial ischemia and reperfusion in a rat model." Circulation. 95. 2552-2558 (1997)
[文献書誌] Yamada T, et al.: "Indium-111 antimyosin antibody imaging and thallium-201 imaging:A comparative myocardial scintigraphic study using SPECT in patients with myocarditis and dilated cardiomyopathy." Jpn Circ J. 61. 827-835 (1997)
[文献書誌] Matsumori A, et al.: "Modulation of cytokine production and protection against lethal endotoxemia by the cardiac glycoside ouabain." Circulation. 96. 1501-1506 (1997)
[文献書誌] Matsumori A, et al.: "Amiodarone inhibits production of tumor necrosis factor-α by human mononuclear cells.A possible mechanism for its effect in heart failure." Circulation. 96. 1386-1389 (1997)
[文献書誌] Shioi T, et al.: "Increased expression of interleukin-1 β and monocyle chemotactic and activating factor(MCAF)/monocyte chemoattractant protein-1(MCP-1)in the hypertrophied and failing heart with pressure overload." Circ Res. 81. 664-671 (1997)
[文献書誌] Sasayama S, et al.: "Immunomodulatory therapy and survival with cardiac disease." Heart Failure Reviews. 1. 221-227 (1996)
[文献書誌] Sato Y, et al.: "Elevated circulating levels of tumor necrosis factor in patients with mitral valve disease and ventricular septum defect." Heart Vessels. 11. 218-220 (1996)
[文献書誌] Wang W-Z, et al.: "Beneficial cffects of amlodipine in a murine model of congestive heart failure induced by viral myocarditis:A possible mechanism through inhibition of nitric oxide production." Circulation. 95. 245-251 (1997)
[文献書誌] Matsumori A.: "Implications of cytokine inhibition for the drug therapy of heart failure." Bio Drugs. 7. 107-118 (1997)
[文献書誌] Hirozane T, et al.: "Prolongation of murine cardiac allograft survival with vesnarinone." J Mol Cell Cardiol. 29. 67-76 (1997)
[文献書誌] Matsumori A, et al.: "Plasma levels of the monocyte chemotactic and activating factor/monocyte chemotactic protein-1 are elevated in patients with acute myocardial infarction." J Mol Cell Cardiol. 29. 419-423 (1997)
[文献書誌] Sato Y, et al.: "Measuring serum aminoterminal type III procollagen peptide,7S domain of type IV collagen,and cardiac troponin T in patients with idiopathic dilated cardiomyopathy and secondary cardiomyopathy." HEART. 78. 505-508 (1997)
[文献書誌] Shioi T, et al.: "Protective role of Interleukin-12 in viral myocarditis." J Mol Cell Cardiol. 29. 2327-2334 (1997)
[文献書誌] Matsumori A.: "Calcium channel blocker-induced protection against cardiovascular damage." Int.J.Cardiol.62. S39-S46 (1997)
[文献書誌] Matsumori A.: "The use of cytokine inhibitors A new therapeutic insight into heart failure." Int.J.Cardiol.62. S3-S12 (1997)
[文献書誌] Matsumori A, et al.: "Edited by Sasayama S,Springer-Verlag,Tokyo" Cytokines and heart failure:Immunomodulating agents for the management of heart failure.In New Horizons for Failing Heart Syndrome,14 (1996)
[文献書誌] Sasayama S, et al.: "Edited by Endoh M,Morad M,Scholz H,Iijima T,Springer-Verlag,Tokyo" Immunomodulating effects as new aspects of a positive inotropic agent.In Molecular and Cellular Mechanism of Cardiovascular Regulation,11 (1996)

1997 年度 実績報告書

動脈硬化症を中心とした心血管系における遺伝子治療法の開発

研究代表者

篠山 重威 京都大学, 医学研究科, 教授 (70109007)

研究成果

[文献書誌] Furukawa Y, et al.: "Angiotensin II receptor antagonist TCV-116 reduces gerft coronary artery disease and preserves graft status in a murine model." Circulation. 93. 333-339 (1996)

[文献書誌] Sasayama S, et al.: "Role of cytokines in the syndrome of heart failure." Int Med. 35. 60-63 (1996)

[文献書誌] Matsumori A, et al.: "Increased circulating hepatocyte growth factor in the early stage of acute myocardial infarction" Biochem Biophys Res Commun. 221. 391-395 (1996)

[文献書誌] Furukawa Y, et al.: "Immunomodulation by an adenylate cyclase activator,NKH477,in vivo and in vitro." Clin Immunol Immunopathol. 79. 25-35 (1996)

[文献書誌] Hasegawa K, et al.: "Endothelin-1 and its receptor in hypertrophic cardiomyopathy." Hypertension. 27. 254-264 (1996)

[文献書誌] Matsumori A, et al.: "Detection of hepatitis C virus RNA from the heart of patients with hypertrophic cardiomyopathy." Biochem Biophys Res Commun. 222. 678-682 (1996)

[文献書誌] Matsumori A.: "Cytokines in myocarditis and cardiomyopathies." Curr Opin Cardiol. 11. 302-309 (1996)

[文献書誌] Matsumori A, et al.: "Antimyosin antibody imaging in clinical myocarditis and cardiomyopathy:principle and application." Int J Cardiol. 54. 183-190 (1996)

[文献書誌] Matsumori A, et al.: "Inotropic agents differentially inhibit the induction of nitric oxide synthase by endotoxin in cultured macrophages." Life Sci. 59. PL121-PL125 (1996)

[文献書誌] LiL-X, et al.: "Comparative study of 201TI-scintigraphic image and myocardial pathologic findings in patients with dilated cardiomyopathy." Nucl Med. 10. 307-314 (1996)

[文献書誌] Nakamura H, et al.: "A pathogenic mechanisms of chronic ongoing myocarditis." Jpn Circ J. 60. 609-617 (1996)

[文献書誌] Matsumori A, et al.: "Differential modulation of cytokine production by drugs:Implication for therapy in heart failure." J Mol Cell Cardiol. 28. 2491-2499 (1996)

[文献書誌] Sasayama S, et al.: "Vesnarinone:A Potential Cytokine Inhibitor." J Cardiac Failure. 2. 251-258 (1996)

[文献書誌] Shioi T, et al.: "Persistent expression of cytokine in the chronic stage of viral myocarditis in mice." Circulation. 94. 2930-2937 (1996)

[文献書誌] Matsumori A, et al.: "Newer aspects of pathogenesis of heart failure:Hepatitis C virus infection in myocarditis and cardiomyopathy." J Cardiac Failure. 2. S187-S194 (1996)

[文献書誌] Sasayama S, et al.: "Immunomodulation:A new horizon for medical treatment of heart failure." J Cardiac Failure. 2. S287-S294 (1996)

[文献書誌] Tadamura E, et al.: "Myocardial metabolic changes in hypertrophic cardiomyopathy." J Nucl Med. 37. 572-577 (1996)

[文献書誌] Nakamura H, et al.: "Autoimmune respones in chronic ongoing myocarditis demonstrated by heterotopic cardiac transplantation in mice." Circulation. 94. 3348-3354 (1996)

[文献書誌] Matsumori A.: "Molecular and immune mechanisms in the pathogenesis of cardiomyopathy." Jpn Circ J. 61. 275-291 (1997)

[文献書誌] Ono K, et al.: "Enhanced expression of hepatocyte growth factor/c-met by myocardial ischemia and reperfusion in a rat model." Circulation. 95. 2552-2558 (1997)

[文献書誌] Yamada T, et al.: "Indium-111 antimyosin antibody imaging and thallium-201 imaging:A comparative myocardial scintigraphic study using SPECT in patients with myocarditis and dilated cardiomyopathy." Jpn Circ J. 61. 827-835 (1997)

[文献書誌] Matsumori A, et al.: "Modulation of cytokine production and protection against lethal endotoxemia by the cardiac glycoside ouabain." Circulation. 96. 1501-1506 (1997)

[文献書誌] Matsumori A, et al.: "Amiodarone inhibits production of tumor necrosis factor-α by human mononuclear cells.A possible mechanism for its effect in heart failure." Circulation. 96. 1386-1389 (1997)

[文献書誌] Shioi T, et al.: "Increased expression of interleukin-1 β and monocyle chemotactic and activating factor(MCAF)/monocyte chemoattractant protein-1(MCP-1)in the hypertrophied and failing heart with pressure overload." Circ Res. 81. 664-671 (1997)

[文献書誌] Sasayama S, et al.: "Immunomodulatory therapy and survival with cardiac disease." Heart Failure Reviews. 1. 221-227 (1996)

[文献書誌] Sato Y, et al.: "Elevated circulating levels of tumor necrosis factor in patients with mitral valve disease and ventricular septum defect." Heart Vessels. 11. 218-220 (1996)

[文献書誌] Wang W-Z, et al.: "Beneficial cffects of amlodipine in a murine model of congestive heart failure induced by viral myocarditis:A possible mechanism through inhibition of nitric oxide production." Circulation. 95. 245-251 (1997)

[文献書誌] Matsumori A.: "Implications of cytokine inhibition for the drug therapy of heart failure." Bio Drugs. 7. 107-118 (1997)

[文献書誌] Hirozane T, et al.: "Prolongation of murine cardiac allograft survival with vesnarinone." J Mol Cell Cardiol. 29. 67-76 (1997)

[文献書誌] Matsumori A, et al.: "Plasma levels of the monocyte chemotactic and activating factor/monocyte chemotactic protein-1 are elevated in patients with acute myocardial infarction." J Mol Cell Cardiol. 29. 419-423 (1997)

[文献書誌] Sato Y, et al.: "Measuring serum aminoterminal type III procollagen peptide,7S domain of type IV collagen,and cardiac troponin T in patients with idiopathic dilated cardiomyopathy and secondary cardiomyopathy." HEART. 78. 505-508 (1997)

[文献書誌] Shioi T, et al.: "Protective role of Interleukin-12 in viral myocarditis." J Mol Cell Cardiol. 29. 2327-2334 (1997)

[文献書誌] Matsumori A.: "Calcium channel blocker-induced protection against cardiovascular damage." Int.J.Cardiol.62. S39-S46 (1997)

[文献書誌] Matsumori A.: "The use of cytokine inhibitors A new therapeutic insight into heart failure." Int.J.Cardiol.62. S3-S12 (1997)

[文献書誌] Matsumori A, et al.: "Edited by Sasayama S,Springer-Verlag,Tokyo" Cytokines and heart failure:Immunomodulating agents for the management of heart failure.In New Horizons for Failing Heart Syndrome,14 (1996)

[文献書誌] Sasayama S, et al.: "Edited by Endoh M,Morad M,Scholz H,Iijima T,Springer-Verlag,Tokyo" Immunomodulating effects as new aspects of a positive inotropic agent.In Molecular and Cellular Mechanism of Cardiovascular Regulation,11 (1996)

1997 年度実績報告書

篠山重威京都大学, 医学研究科, 教授 (70109007)