1998 年度実績報告書

HGFならびにLIMキナーゼによる高次細胞機能の調節とがん特性の研究

研究課題

研究課題/領域番号	06283216
研究機関	大阪大学
研究代表者	中村敏一大阪大学, 医学部, 教授 (00049397)
研究分担者	宮本一政大阪大学, 医学部, 助手 (60273679) 小清水右一大阪大学, 医学部, 助手 (50281126)
キーワード	HGF / HGFアンタゴニスト / 腫瘍血管新生 / 脂肪肝 / 肝硬変 / 慢性腎不全 / 心筋梗塞 / 遺伝子治療
研究概要	1. 私たちはこれまでIIGFの生物活性をほぼ完全にブロックするアンタゴニスト分子(HGF/NK4)の作製に成功し、HGF/NK4が種々の癌細胞の増殖や浸潤を著しく抑制することを明らかにしてきたが、新たにHGF/NK4にはそれ単独で血管新生抑制因子としての活性を有していることを見い出した。そのためHGF/NK4を投与することにより、ヌードマウス皮下に移植したLewis肺癌細胞等の癌細胞が誘起する腫瘍血管新生は強力に抑制され、その遠隔臓器への転移も著しく阻害された。2. ラットにエタノール含飼料を与えると脂肪肝を発症するが、その際、肝組織におけるHGFの発現が強くなっており、脂肪肝の発症・進行過程におけるHGFの関与が強く示唆された。そこで脂肋肝を誘起したラットにリコンビナントHGFを7日間投与したところ、対照群では脂肪肝が顕著に進行するのに対し、HGF投与動物では肝細胞中の脂肪滴の著しい減少、および肝機能の回復が認められた。 3. HVJ-リポソーム法を用いて肝硬変に対するHGF遺伝子治療を行った。肝臓毒であるDMNをラットに投与すると約4週で肝硬変が発症し、7週以内で全例が死亡したが、ヒトHGF遺伝子を骨格筋に導入したラットでは顕著な肝細胞死の抑制、再生促進に伴い肝機能の著しい回復がみられ、全例が生存した。 4. ネフローゼ自然発症マウスでは間質線維化の初期過程ではHGFの強い発現が認められるが、その進行に伴いHGFの枯渇が認められる。またこのマウスにHGFの中和抗体を投与すると通常よりも急激な間質線維化の進行が見られる一方、HGFを投与することによりネフローゼの発症抑制、ならびに腎機能の改善が認められた。 5. ラットに左冠動脈結紮-再潅流を施し作製した急性心筋梗塞モデルでは、HGF投与により再潅流後の梗塞領域は対照群に比べて明らかに縮小し、心筋細胞死も顕著に減少しており、HGFは虚血-再潅流時における心筋細胞死に対して抑制効果をもつことが示された。

研究成果
(34件)

すべてその他

すべて文献書誌 (34件)

[文献書誌] M.T.Donato et al.: "Human hepatocyte growth factor down regulated the expression of cytochrome P450 isozymes in human hepatocytes in primaoy culture." J.Pharmacl Exp.Therap.284. 760-767 (1998)
[文献書誌] Y.Yo et al.: "Actions of hepatocyte growth factor as a local modulator in the kidney:Potential role in pathogenesis of renal disease." Kindney Intern.53. 50-58 (1998)
[文献書誌] D.Schuppan et al.: "Collagens in the liver extracellular matrix hepatocyte growth factor." Gastroenterology.114. 139-152 (1998)
[文献書誌] M.Lyon et al.: "Hepatocyte growth factor/scatter factor binds with high affinity to dermatan sulphate." J.Biol.Chem.273. 271-278 (1998)
[文献書誌] H.Li et al.: "Hepatocyte gorwht factor stimuolates invasion of gallbladder carcinoma cell lines in vitro." Clin.Exp.Metastasis.16. 74-82 (1998)
[文献書誌] S.Nakamura et al.: "A Novel vascular modulator,hepatocyte growth factor(HGF),as a potentlal index of the severity of hypertention." Biochem.Biophys.Res.Commun.242. 238-243 (1998)
[文献書誌] K.Liu et al.: "Protamine enhances the proliferative activity of hepatocyte growth factor in rats." Am.J.Physiol.274. G21-G28 (1998)
[文献書誌] R.Gal-Levi et al.: "Hepatocyte growth factor plays a dual role in regulating skeletal muscle satellite cell proliferation and differentiation." Biochem.Biophys.Acta.1402. 39-51 (1998)
[文献書誌] T.Miyazawa et al.: "Protection of hippocampal neurons from ischemia-induced delayed neuronal death by hepatocyte growth factor:A novel neurotrophic factor." J.Celebral Blood Flow Metabolism.18. 345-348 (1998)
[文献書誌] H.Ohmichi et al.: "Hepatocyte growth factor(HGF)acts as a mesenchynal-derived morphogenic factor during fetal lung develpment." Development.125. 1315-1324 (1998)
[文献書誌] S.Mizuno et al.: "Hepatocyte growth factor prevents renal fibrosis and dysfunction in a mouse model of chronio renal-disease." J.Clin.Invest.101. 1827-1834 (1998)
[文献書誌] S.Yi et al.: "Paracrine effects of hepatocyte growth factor/scatter factor on non-small cell lung carcinoma cell lines." Brit.J.Cancer.77. 2162-2170 (1998)
[文献書誌] K.Kosai et al.: "Hepatocyte growth factor abrogates Fas-induced lethal liver apoptosis i mice." Biochem.Biophys.Res.Commun.244. 683-690 (1998)
[文献書誌] M.Suzuki et al.: "Stimulation by histamine of TPA-dependent hepatocyte growth factor production in promyelocytic leukemia HL-60 cells." Biosci.Biotechnol.Biochem.62. 1399-1402 (1998)
[文献書誌] S.Tanimura et al.: "Activation of the 41-/43 kDa mitogen-activated protein kinase signaling pathway is required for hepatocyte growth factor-induced cell scattering." Oncogene. 17. 57-65 (1998)
[文献書誌] T.Motoi et al.: "Coexpression of hepatocyte growth factor and c-met proto-oncogene product in synovialsarcoma." Pathology Intern.48. 769-775 (1998)
[文献書誌] K.Matsumoto et al.: "Cooperative interaction between α-chain and β-chain of HGF on c-Met receptor confers ligand-induced receptor lyrosine phosphorylation." J.Biol.Chem.273. 22913-22920 (1998)
[文献書誌] K.Date et al.: "Inhibition of tumor growth and invasion by a four-kringle antagonist(HGF/NK4)for hepatocyte growth factor." Oncogene. 17. 3045-3054 (1998)
[文献書誌] Y.Yo et al.: "Potential role of hepatocyte growth factor in the maintenance of renal structure:Anti-apoptotic action of HGF on epithelial cells." Kidney Intern.54. 1128-1138 (1998)
[文献書誌] K-X.Liu et al.: "Ligand-induced down-regulation of receptor-mediated clearance of hepatocyte growth factor in rats." Am.J.Physiol.274. G21-G28 (1998)
[文献書誌] N.Nakano et al.: "Negative regulation of local hepatocyte growth factor(HGF)expression by angiotensin II and transforming growth[actor-β in blood vessels." Hypertension. 32. 444-451 (1998)
[文献書誌] H.Takahashi et al.: "A novel transcript encoding truncated LIM-kinase 2 is specifically expressed in male germ cells undergaing meiosis." Biochem.Biophys.Res.Commun.249. 138-145 (1998)
[文献書誌] R.Paciucci et al.: "Activation of the UPA/UPA-R system and redistribution of E-cadherin are associated with HGF-induced motility of pancreas tumor cells." Am.J.Pathol.153. 201-212 (1998)
[文献書誌] A.Jikkoet al.: "The role of hepatocyte growth factor in growth plate cartilage." J.Bone Miner.Metab.16. 170-177 (1998)
[文献書誌] K.Sugahara et al.: "Elevation of serum human hepatocyte growth factor (HGF) level in patients with pneumonectomy during perioperative period." Intensive Care Med.24. 434-437 (1998)
[文献書誌] I.Weimar et al.: "Hepatocyte growth factor/scatter factor(HGF/SF)affects proliferation and migration of myeloid leukemic cells." Leukemia. 12. 1195-1203 (1998)
[文献書誌] A.Bosch et al.: "Effects of keratinocyte and hepatocyte growth factor in vivo:Implications for retroviral-mediated gene transfer to liver." Human Gene Therapy. 9. 1747-1754 (1998)
[文献書誌] S.Nakamura et al.: "Hepatocyte growth factor as a potential index of complication in diabetes mellitus." J.Hypertension. 16. 2019-2026 (1998)
[文献書誌] T.Ueki et al.: "Hepatocyte growth factor gene therapy of liver cirrhosis in rats" Nature Medicine. 5. 226-230 (1999)
[文献書誌] Y.Liu et al.: "Upregulation of hepatocyte growth factor receptor:an amplification and targeting mechanism for hepatocyte growth factor action in acute renal failure." Kidney Intern.55. 442-453 (1999)
[文献書誌] M.Tahara et al.: "Hepatocyte gowth factor leads to recovery from alcohol-induced fatty liver in rats." J.Clin.Invest.103. 313-320 (1999)
[文献書誌] K.Matsumoto & T.Nakamura: "Hepatocyte growth factor and Met:Molecular dialogue for tissue organization and repair." Korean J.Biol.Sci.2. 1-8 (1998)
[文献書誌] 中村敏一他: "HGFの分子医学-病態生理・診断・治療-" メディカルレビュー社, 221 (1998)
[文献書誌] K.Matsumoto & T.Nakamura: "The Proceedings of the Second International Symposium of Tissue Engineering for Therapeutic Use.(in press)" Churchill Livingstone, (1998)

1998 年度 実績報告書

HGFならびにLIMキナーゼによる高次細胞機能の調節とがん特性の研究

研究代表者

中村 敏一 大阪大学, 医学部, 教授 (00049397)

研究成果

[文献書誌] M.T.Donato et al.: "Human hepatocyte growth factor down regulated the expression of cytochrome P450 isozymes in human hepatocytes in primaoy culture." J.Pharmacl Exp.Therap.284. 760-767 (1998)

[文献書誌] Y.Yo et al.: "Actions of hepatocyte growth factor as a local modulator in the kidney:Potential role in pathogenesis of renal disease." Kindney Intern.53. 50-58 (1998)

[文献書誌] D.Schuppan et al.: "Collagens in the liver extracellular matrix hepatocyte growth factor." Gastroenterology.114. 139-152 (1998)

[文献書誌] M.Lyon et al.: "Hepatocyte growth factor/scatter factor binds with high affinity to dermatan sulphate." J.Biol.Chem.273. 271-278 (1998)

[文献書誌] H.Li et al.: "Hepatocyte gorwht factor stimuolates invasion of gallbladder carcinoma cell lines in vitro." Clin.Exp.Metastasis.16. 74-82 (1998)

[文献書誌] S.Nakamura et al.: "A Novel vascular modulator,hepatocyte growth factor(HGF),as a potentlal index of the severity of hypertention." Biochem.Biophys.Res.Commun.242. 238-243 (1998)

[文献書誌] K.Liu et al.: "Protamine enhances the proliferative activity of hepatocyte growth factor in rats." Am.J.Physiol.274. G21-G28 (1998)

[文献書誌] R.Gal-Levi et al.: "Hepatocyte growth factor plays a dual role in regulating skeletal muscle satellite cell proliferation and differentiation." Biochem.Biophys.Acta.1402. 39-51 (1998)

[文献書誌] T.Miyazawa et al.: "Protection of hippocampal neurons from ischemia-induced delayed neuronal death by hepatocyte growth factor:A novel neurotrophic factor." J.Celebral Blood Flow Metabolism.18. 345-348 (1998)

[文献書誌] H.Ohmichi et al.: "Hepatocyte growth factor(HGF)acts as a mesenchynal-derived morphogenic factor during fetal lung develpment." Development.125. 1315-1324 (1998)

[文献書誌] S.Mizuno et al.: "Hepatocyte growth factor prevents renal fibrosis and dysfunction in a mouse model of chronio renal-disease." J.Clin.Invest.101. 1827-1834 (1998)

[文献書誌] S.Yi et al.: "Paracrine effects of hepatocyte growth factor/scatter factor on non-small cell lung carcinoma cell lines." Brit.J.Cancer.77. 2162-2170 (1998)

[文献書誌] K.Kosai et al.: "Hepatocyte growth factor abrogates Fas-induced lethal liver apoptosis i mice." Biochem.Biophys.Res.Commun.244. 683-690 (1998)

[文献書誌] M.Suzuki et al.: "Stimulation by histamine of TPA-dependent hepatocyte growth factor production in promyelocytic leukemia HL-60 cells." Biosci.Biotechnol.Biochem.62. 1399-1402 (1998)

[文献書誌] S.Tanimura et al.: "Activation of the 41-/43 kDa mitogen-activated protein kinase signaling pathway is required for hepatocyte growth factor-induced cell scattering." Oncogene. 17. 57-65 (1998)

[文献書誌] T.Motoi et al.: "Coexpression of hepatocyte growth factor and c-met proto-oncogene product in synovialsarcoma." Pathology Intern.48. 769-775 (1998)

[文献書誌] K.Matsumoto et al.: "Cooperative interaction between α-chain and β-chain of HGF on c-Met receptor confers ligand-induced receptor lyrosine phosphorylation." J.Biol.Chem.273. 22913-22920 (1998)

[文献書誌] K.Date et al.: "Inhibition of tumor growth and invasion by a four-kringle antagonist(HGF/NK4)for hepatocyte growth factor." Oncogene. 17. 3045-3054 (1998)

[文献書誌] Y.Yo et al.: "Potential role of hepatocyte growth factor in the maintenance of renal structure:Anti-apoptotic action of HGF on epithelial cells." Kidney Intern.54. 1128-1138 (1998)

[文献書誌] K-X.Liu et al.: "Ligand-induced down-regulation of receptor-mediated clearance of hepatocyte growth factor in rats." Am.J.Physiol.274. G21-G28 (1998)

[文献書誌] N.Nakano et al.: "Negative regulation of local hepatocyte growth factor(HGF)expression by angiotensin II and transforming growth[actor-β in blood vessels." Hypertension. 32. 444-451 (1998)

[文献書誌] H.Takahashi et al.: "A novel transcript encoding truncated LIM-kinase 2 is specifically expressed in male germ cells undergaing meiosis." Biochem.Biophys.Res.Commun.249. 138-145 (1998)

[文献書誌] R.Paciucci et al.: "Activation of the UPA/UPA-R system and redistribution of E-cadherin are associated with HGF-induced motility of pancreas tumor cells." Am.J.Pathol.153. 201-212 (1998)

[文献書誌] A.Jikkoet al.: "The role of hepatocyte growth factor in growth plate cartilage." J.Bone Miner.Metab.16. 170-177 (1998)

[文献書誌] K.Sugahara et al.: "Elevation of serum human hepatocyte growth factor (HGF) level in patients with pneumonectomy during perioperative period." Intensive Care Med.24. 434-437 (1998)

[文献書誌] I.Weimar et al.: "Hepatocyte growth factor/scatter factor(HGF/SF)affects proliferation and migration of myeloid leukemic cells." Leukemia. 12. 1195-1203 (1998)

[文献書誌] A.Bosch et al.: "Effects of keratinocyte and hepatocyte growth factor in vivo:Implications for retroviral-mediated gene transfer to liver." Human Gene Therapy. 9. 1747-1754 (1998)

[文献書誌] S.Nakamura et al.: "Hepatocyte growth factor as a potential index of complication in diabetes mellitus." J.Hypertension. 16. 2019-2026 (1998)

[文献書誌] T.Ueki et al.: "Hepatocyte growth factor gene therapy of liver cirrhosis in rats" Nature Medicine. 5. 226-230 (1999)

[文献書誌] Y.Liu et al.: "Upregulation of hepatocyte growth factor receptor:an amplification and targeting mechanism for hepatocyte growth factor action in acute renal failure." Kidney Intern.55. 442-453 (1999)

[文献書誌] M.Tahara et al.: "Hepatocyte gowth factor leads to recovery from alcohol-induced fatty liver in rats." J.Clin.Invest.103. 313-320 (1999)

[文献書誌] K.Matsumoto & T.Nakamura: "Hepatocyte growth factor and Met:Molecular dialogue for tissue organization and repair." Korean J.Biol.Sci.2. 1-8 (1998)

[文献書誌] 中村敏一他: "HGFの分子医学-病態生理・診断・治療-" メディカルレビュー社, 221 (1998)

[文献書誌] K.Matsumoto & T.Nakamura: "The Proceedings of the Second International Symposium of Tissue Engineering for Therapeutic Use.(in press)" Churchill Livingstone, (1998)

1998 年度実績報告書

中村敏一大阪大学, 医学部, 教授 (00049397)