2002 Fiscal Year Annual Research Report

生体内での「機能的」血管新生過程における細胞・分子間作用階層構造の解明〜生体内遺伝子導入方による個体での検証〜

Research Project

Project/Area Number	14370072
Research Institution	Kyushu University
Principal Investigator	米満吉和九州大学, 医学部附属病院, 助手 (40315065)
Co-Investigator(Kenkyū-buntansha)	中川和憲九州大学, 大学院・医学研究院, 講師 (50217668) 中島豊九州大学, 大学院・医学研究院, 助教授 (50135349) 居石克夫九州大学, 大学院・医学研究院, 教授 (70108710)
Keywords	センダイウイルスペクター / 遺伝子治療 / FGF-2 / VEGF / HGF / 重症虚血肢
Research Abstract	本研究初年度は、昨年度得られた知見「虚血肢に対する遺伝子治療には、欧米で使用されているVEGFよりFGF-2の方が効果が高く、かつ安全域が広い(Circ Res 2002(1))を基に、そのメカニズム解析を行った。主に「何故、FGF-2の過剰発現が機能的に成熟した血管新生に至るのか」について、特にその他の血管新生因子HGF、VEGF-C、さらには間葉系細胞の増殖因子であるPDGFの役割を中心に検討した。 1.HGFについて FGF-2は虚血状態に依存せず内因性HGFを強く誘導すること、そのシグナルとしてp44/42MAPK系、Ras系、p70S6K系が重要であること、そしてそのmediatorとして、PDGF-AAが重要であることを見い出した(Circ Res 2002(2))。 2.PDGF-AAについて血管内皮細胞には直接的に作用しないPDGF-AAは、血管新生過程においてHGFのみならずVEGFの発現持続にも重要な役割を果していることを明らかにした。PDGF-AAの活性中和により、FGF-2依存性血管新生は阻害されることを見い出した(論文準備中)。 3.VEGF-Cについてリンパ管新生因子VEGF-Cは血管新生にとっても重要な役割、つまり血管構築に必須であることを見い出した(論文準備中)。この作用は血管内皮細胞に直接作用しないPDGF-BBを介した、周皮細胞の遊走に依存していることを明らかにした。 4.Angiopoietin-Tie2糸について内皮細胞だけでなく間葉糸細胞にもTie-2が発現していることを証明し、特にEGF-like domainを欠く新しいalternative splicing formのクローニングに成功した(GeneBankに登録済み)。糖尿病では他の血管新生因子と比較して、Ang-Tie2糸の発現が著明に低下していることを証明した。以上のごとく、我々のコンセプト「機能的血管新生誘導過程における血管新生因子の階層的制御機構」という新しい観点から、各分子の様々な新しい機能的連関が明らかになりつつある。今後も検討を進めて行く予定である。

Research Products

(35 results)

All Other

All Publications (35 results)

[Publications] Ishida M, et al.: "Immunohistochemical phenotypic alterations of rabbit autologous vein grafts implanted under arterial circulation with or without poor distal runoff-implications of vein graft remodeling"Atherosclerosis. 154. 345-354 (2001)
[Publications] Masaki I, et al.: "Recombinant Sendai Virus-mediated Gene Transfer to Vasculature : a new class of efficient gene transfer vector to the vascular system"The FASEB Journal. 15. 1294-1296 (2001)
[Publications] Teramoto N, et al.: "Dual action of ZD6169, a novel K+channel opener, on ATP-sensitive K+channels in pig urethral myocytes"British Journal of Pharmacology. 133. 154-164 (2001)
[Publications] Komori K, et al.: "Non-penetrating vascular clips anastomosis inhibited intimal thickening under poor runoff conditions in canine autogenous vein grafts"European Journal of Vascular and Endovascular Surgery. 21. 241-247 (2001)
[Publications] Hasegawa H, et al.: "Preclinical and therapeutic utility of HVJ-liposomes as a gene transfer vector for hepatocellular carcinoma using herpes simplex thymidine kinase"Cancer Gene Therapy. 8. 252-258 (2001)
[Publications] Koga T, et al.: "Heterogenous distribution of p53 immunoreactivity in human lung adenocarcinoma correlates with MDM2 protein expression, rather than with p53 gene mutation"International Journal of Cancer. 95. 232-239 (2001)
[Publications] Koga T, et al.: "Clinico-pathological and molecular evidence indicating the independency of bronchio-alveolar components from other subtypes of human lung adenocarcinoma"Clinical Cancer Research. 7. 1730-1738 (2001)
[Publications] Matsumoto T, et al.: "Successful and optimized in vivo gene transfer to rabbit carotid artery mediated by electronic pulse"Gene Therapy. 8. 1174-1179 (2001)
[Publications] Yamashita A, et al.: "Fibroblast growth factor-2 determines severity of joint disease in adjuvantinduced arthritis rats"The Journal of Immunology. 168. 450-457 (2002)
[Publications] Kume M, et al.: "Administration of a decoy against the Ap-1 binding site suppresses neointimal thickening in rabbit balloon injured arteries"Circulation. 105. 1226-1232 (2002)
[Publications] Ikeda Y, et al.: "Recombinant Sendai virus-mediated gene transfer to the retinal tissue of adult rats : efficient gene transfer by brief exposure"Experimental Eye Research. 75. 39-48 (2002)
[Publications] Koga T, et al.: "Lung adenocarcinoma with bronchio-alveolar carcinoma component frequently associates foci of high grade atypical adenomatous"American Journal of Clinical Pathology. 117. 464-470 (2002)
[Publications] Ohta S, et al.: "Intraluminal gene transfer of endothelial nitric oxide synthase partially supresses neointimal formation of vein grafts of hypercholesterolemic rabbits : a limited biological effect as a result of the loss of medical smooth muscle cells"Surgery. 131. 644-653 (2002)
[Publications] Masaki I, et al.: "Gene therapy for experimental critical limb ischemia : acceleration of limb loss by overexpression of VEGF165, but not of FGF-2"Circulation Research. 90. 966-973 (2002)
[Publications] Jiang C, et al.: "Gene transfer into brain capillary endothelial cells in vitro and in vivo with HVJ-liposomes"The Journal of Drug Targeting. 10. 345-352 (2002)
[Publications] Kanna T, et al.: "Effects of sevoflurane on brandykinin-induced calcium mobilization in pulmonary arterial valvular endothelial cells situ : Sevoflurane Stimulates Plasmalemmal Calcium Influx Into Endothelial Cells"The Journal of Cardiovascular Pharmacology. 40. 714-724 (2002)
[Publications] Ikeda Y, et al.: "Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Attenuates Pulmonary Hypertension in Rats"American Journal of Physiology, Heart and Circulatory Physiology. 283. H2021-2028 (2002)
[Publications] Onimaru M, et al.: "FGF-2 gene transfer can stimulate HGF expression, irrespective of hypoxia-mediated downregulation in ischemic limb"Circulation Research. 91. 723-730 (2002)
[Publications] 坂本泰二, 他: "網膜への遺伝子ターゲティング(Gene Targeting to Retina)"あたらしい眼科. 18. 41-46 (2001)
[Publications] 真崎一郎, 他: "Trend Paper:組換えセンダイウイルスベクターによる遺伝子治療:純国産ベクターは遺伝子治療に新しい道を開くか?"バイオ・ベンチャー. 1. 85-88 (2001)
[Publications] Yonemitsu Y, et al.: "Gene Therapy in Vascular Surgery Comes of Age"Surgery. 131. S261-S268 (2002)
[Publications] 庄司文裕, 他: "組換えセンダイウイルスベクターを用いた血管壁への遺伝子導入"脳と循環. 7. 52-56 (2002)
[Publications] 米満吉和, 他: "特集「大動脈炎症候群をどう診るか」 10.ウイルス感染と血管炎"Heart View. 6. 88-93 (2002)
[Publications] 米満吉和, 他: "Suggestion:「機能的」血管新生療法の確立に向けて"治療学. 36. 471 (2002)
[Publications] Shoji F, et al.: "Airway-directed gene transfer of interleukin-10 using recombinant Sendai virus effectively prevents post-transplantation bronchiolitis obliterans in mice"Gene Therapy. 10. 213-218 (2003)
[Publications] Jin CH, et al.: "Recombinant Sendai virus provides highly efficient gene transfer into human cord blood-derived hematopoietic stem cells"Gene Therapy. 10. 272-280 (2003)
[Publications] Sakamoto T, et al.: "Gene targeting to the retina"Advanced Drug Delivery Reviews. 52. 93-102 (2001)
[Publications] 米満吉和, 他: "わだい:サイトメガロウイルスと動脈硬化"Medical Technology. 29. 386-388 (2001)
[Publications] 居石克夫, 他: "血管壁細胞の遺伝子発現制御と治療への応用"脈管学. 41. 501-509 (2001)
[Publications] 米満吉和, 他: "ウイルス感染と大型血管炎"脈管学. 41. 381-390 (2001)
[Publications] 米満吉和, 他: "血管新生遺伝子治療における「血管新生因子作用機構の階層性」と「モIntegratedモ Therapeutic Angiogenesis」の提唱"脈管学. 42. 381-389 (2002)
[Publications] 山下彰久, 他: "特集「血液細胞と血管新生」 8.遺伝子導入による血管新生療法"血液フロンティア. 12. 803-811 (2002)
[Publications] 宮崎勝徳, 他: "特集:遺伝子治療-現状とその近未来。遺伝子治療前臨床研究の現状:14.センダイウイルスベクター組換えセンダイウイルスベクターによる遺伝子治療臨床研究計画"医学のあゆみ. 203. 564-569 (2002)
[Publications] 池田康博, 他: "「医学研究再入門」第5回:個体レベルの遺伝子導入"分子心血管病. 3. 609-617 (2002)
[Publications] Yamaguchi S, et al.: "A traumatic pseudoaneurysm of the dorsalis pedis artery : report of a case"Surg Today. 32. 756-757 (2002)

2002 Fiscal Year Annual Research Report

生体内での「機能的」血管新生過程における細胞・分子間作用階層構造の解明 〜生体内遺伝子導入方による個体での検証〜

Principal Investigator

米満 吉和 九州大学, 医学部附属病院, 助手 (40315065)

Research Products

[Publications] Ishida M, et al.: "Immunohistochemical phenotypic alterations of rabbit autologous vein grafts implanted under arterial circulation with or without poor distal runoff-implications of vein graft remodeling"Atherosclerosis. 154. 345-354 (2001)

[Publications] Masaki I, et al.: "Recombinant Sendai Virus-mediated Gene Transfer to Vasculature : a new class of efficient gene transfer vector to the vascular system"The FASEB Journal. 15. 1294-1296 (2001)

[Publications] Teramoto N, et al.: "Dual action of ZD6169, a novel K+channel opener, on ATP-sensitive K+channels in pig urethral myocytes"British Journal of Pharmacology. 133. 154-164 (2001)

[Publications] Komori K, et al.: "Non-penetrating vascular clips anastomosis inhibited intimal thickening under poor runoff conditions in canine autogenous vein grafts"European Journal of Vascular and Endovascular Surgery. 21. 241-247 (2001)

[Publications] Hasegawa H, et al.: "Preclinical and therapeutic utility of HVJ-liposomes as a gene transfer vector for hepatocellular carcinoma using herpes simplex thymidine kinase"Cancer Gene Therapy. 8. 252-258 (2001)

[Publications] Koga T, et al.: "Heterogenous distribution of p53 immunoreactivity in human lung adenocarcinoma correlates with MDM2 protein expression, rather than with p53 gene mutation"International Journal of Cancer. 95. 232-239 (2001)

[Publications] Koga T, et al.: "Clinico-pathological and molecular evidence indicating the independency of bronchio-alveolar components from other subtypes of human lung adenocarcinoma"Clinical Cancer Research. 7. 1730-1738 (2001)

[Publications] Matsumoto T, et al.: "Successful and optimized in vivo gene transfer to rabbit carotid artery mediated by electronic pulse"Gene Therapy. 8. 1174-1179 (2001)

[Publications] Yamashita A, et al.: "Fibroblast growth factor-2 determines severity of joint disease in adjuvantinduced arthritis rats"The Journal of Immunology. 168. 450-457 (2002)

[Publications] Kume M, et al.: "Administration of a decoy against the Ap-1 binding site suppresses neointimal thickening in rabbit balloon injured arteries"Circulation. 105. 1226-1232 (2002)

[Publications] Ikeda Y, et al.: "Recombinant Sendai virus-mediated gene transfer to the retinal tissue of adult rats : efficient gene transfer by brief exposure"Experimental Eye Research. 75. 39-48 (2002)

[Publications] Koga T, et al.: "Lung adenocarcinoma with bronchio-alveolar carcinoma component frequently associates foci of high grade atypical adenomatous"American Journal of Clinical Pathology. 117. 464-470 (2002)

[Publications] Ohta S, et al.: "Intraluminal gene transfer of endothelial nitric oxide synthase partially supresses neointimal formation of vein grafts of hypercholesterolemic rabbits : a limited biological effect as a result of the loss of medical smooth muscle cells"Surgery. 131. 644-653 (2002)

[Publications] Masaki I, et al.: "Gene therapy for experimental critical limb ischemia : acceleration of limb loss by overexpression of VEGF165, but not of FGF-2"Circulation Research. 90. 966-973 (2002)

[Publications] Jiang C, et al.: "Gene transfer into brain capillary endothelial cells in vitro and in vivo with HVJ-liposomes"The Journal of Drug Targeting. 10. 345-352 (2002)

[Publications] Kanna T, et al.: "Effects of sevoflurane on brandykinin-induced calcium mobilization in pulmonary arterial valvular endothelial cells situ : Sevoflurane Stimulates Plasmalemmal Calcium Influx Into Endothelial Cells"The Journal of Cardiovascular Pharmacology. 40. 714-724 (2002)

[Publications] Ikeda Y, et al.: "Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Attenuates Pulmonary Hypertension in Rats"American Journal of Physiology, Heart and Circulatory Physiology. 283. H2021-2028 (2002)

[Publications] Onimaru M, et al.: "FGF-2 gene transfer can stimulate HGF expression, irrespective of hypoxia-mediated downregulation in ischemic limb"Circulation Research. 91. 723-730 (2002)

[Publications] 坂本泰二, 他: "網膜への遺伝子ターゲティング(Gene Targeting to Retina)"あたらしい眼科. 18. 41-46 (2001)

[Publications] 真崎一郎, 他: "Trend Paper:組換えセンダイウイルスベクターによる遺伝子治療:純国産ベクターは遺伝子治療に新しい道を開くか?"バイオ・ベンチャー. 1. 85-88 (2001)

[Publications] Yonemitsu Y, et al.: "Gene Therapy in Vascular Surgery Comes of Age"Surgery. 131. S261-S268 (2002)

[Publications] 庄司文裕, 他: "組換えセンダイウイルスベクターを用いた血管壁への遺伝子導入"脳と循環. 7. 52-56 (2002)

[Publications] 米満吉和, 他: "特集「大動脈炎症候群をどう診るか」 10.ウイルス感染と血管炎"Heart View. 6. 88-93 (2002)

[Publications] 米満吉和, 他: "Suggestion:「機能的」血管新生療法の確立に向けて"治療学. 36. 471 (2002)

[Publications] Shoji F, et al.: "Airway-directed gene transfer of interleukin-10 using recombinant Sendai virus effectively prevents post-transplantation bronchiolitis obliterans in mice"Gene Therapy. 10. 213-218 (2003)

[Publications] Jin CH, et al.: "Recombinant Sendai virus provides highly efficient gene transfer into human cord blood-derived hematopoietic stem cells"Gene Therapy. 10. 272-280 (2003)

[Publications] Sakamoto T, et al.: "Gene targeting to the retina"Advanced Drug Delivery Reviews. 52. 93-102 (2001)

[Publications] 米満吉和, 他: "わだい:サイトメガロウイルスと動脈硬化"Medical Technology. 29. 386-388 (2001)

[Publications] 居石克夫, 他: "血管壁細胞の遺伝子発現制御と治療への応用"脈管学. 41. 501-509 (2001)

[Publications] 米満吉和, 他: "ウイルス感染と大型血管炎"脈管学. 41. 381-390 (2001)

[Publications] 米満吉和, 他: "血管新生遺伝子治療における「血管新生因子作用機構の階層性」と「モIntegratedモ Therapeutic Angiogenesis」の提唱"脈管学. 42. 381-389 (2002)

[Publications] 山下彰久, 他: "特集「血液細胞と血管新生」 8.遺伝子導入による血管新生療法"血液フロンティア. 12. 803-811 (2002)

[Publications] 宮崎勝徳, 他: "特集:遺伝子治療-現状とその近未来。遺伝子治療前臨床研究の現状:14.センダイウイルスベクター組換えセンダイウイルスベクターによる遺伝子治療臨床研究計画"医学のあゆみ. 203. 564-569 (2002)

[Publications] 池田康博, 他: "「医学研究再入門」第5回:個体レベルの遺伝子導入"分子心血管病. 3. 609-617 (2002)

[Publications] Yamaguchi S, et al.: "A traumatic pseudoaneurysm of the dorsalis pedis artery : report of a case"Surg Today. 32. 756-757 (2002)

生体内での「機能的」血管新生過程における細胞・分子間作用階層構造の解明〜生体内遺伝子導入方による個体での検証〜

米満吉和九州大学, 医学部附属病院, 助手 (40315065)