1998 Fiscal Year Annual Research Report

HGFによる形態形成機構の分子細胞生物学的研究

Research Project

Project/Area Number	08408027
Research Institution	Osaka University
Principal Investigator	中村敏一大阪大学, 医学部, 教授 (00049397)
Co-Investigator(Kenkyū-buntansha)	船越洋大阪大学, 医学部, 助手 (40273685) 小清水右一大阪大学, 医学部, 助手 (50281126) 宮本一政大阪大学, 医学部, 助手 (60273679)
Keywords	HGF / 脂肪肝 / 肝硬変 / 慢性腎不全 / 心筋梗塞 / 脳虚血 / 遺伝子治療 / トランスジェニックマウス
Research Abstract	1. ラットにエタノール含有飼料を与えると脂肪肝を発症する。脂肪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著しい現象、および肝機能の回復を認めた。 2. HVJ-リポソーム法を用いて肝硬変ラットに対する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。 3. 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HGFの強い発現を認めるが、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みられる一方、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。 4. ラットに左冠動脈結紮一再灌流を施し作製した急性心筋梗塞モデルでは、HGF投与により再灌流後の梗塞領域は対症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は虚血一再灌流時における心筋細胞死に対して抑制効果を持つことが示された。 5. HGFは大脳皮質ニューロンに対し神経栄養因子として働き、グルタミン酸誘導性の神経細胞死を阻止した。 6. 総頚動脈を結紮一再灌流することで一過性脳虚血モデルを作製すると、海馬CAl領域の遅発性神経細胞死を誘起する。この神経細胞死はHGFの持続脳内投与により抑制されることを報告したが、さらに同モデルで発症する大脳皮質の神経細胞死も阻止することを明らかにした。 7.HGFアンタゴニストとしてHGFの分子内断片(HGF/NK4)を作製し、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にはそれ単独で欠陥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。HGF/NK4の投与により、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を強力に阻害し、腫瘍性増殖および転移を強く抑制した。

Research Products
(34 results)

All Other

All Publications (34 results)

[Publications] M.T.Donato et al.: "Human hepatocyle growth factor down regulated the expression of cytochrome P450 isozymes in human hepatocytes in primaoy culture." J.Pharmacl Exp.Therap.284. 760-767 (1998)
[Publications] 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)
[Publications] D.Schuppan et al.: "Collagens in the liver extracellular matrix hepatocyte growth factor." Gastroenterology.114. 139-152 (1998)
[Publications] M.Lyon et al.: "Hepatocyte growth factor/scatter factor binds with high affinity to dermatan sulphate." J.Biol.Chem.273. 271-278 (1998)
[Publications] H.Li et al.: "Hepatocyte gorwht factor stimuolates invasion of gallbladder carcinoma cell lines in vitro." Clin.Exp.Metastasis.16. 74-82 (1998)
[Publications] S.Nakamura et al.: "A Novel vascular modulator,hepatocyte growth factor(HGF),as a potential index of the severity of hypertention." Biochem.Biophys.Res.Commun.242. 238-243 (1998)
[Publications] K.Liu et al.: "Protamine enhances the proliferative activity of hepatocyte growth factor in rats." Am.J.Physiol.274. G21-G28 (1998)
[Publications] 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)
[Publications] 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)
[Publications] H.Ohmichi et al.: "Hepatocyte growth factor(HGF)acts as a mesenchynal-derived morphogenic factor during fetal lung develpment." Development.125. 1315-1324 (1998)
[Publications] 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)
[Publications] 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)
[Publications] K.Kosai et al.: "Hepatocyte growth factor abrogates Fas-induced lethal liver apoptosis in mice." Biochem.Biophys.Res.Commun.244. 683-690 (1998)
[Publications] 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)
[Publications] 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)
[Publications] T.Motoi et al.: "Coexpression of hepatocyte growth factor and c-met proto-oncogene product in synovialsarcoma." Pathology Intern.48. 769-775 (1998)
[Publications] K.Matsumoto et al.: "Cooperative interaction between α-chain and β-chain of HGF on c-Met receptor confers ligand-induced receptor tyrosine phosphorylation." J.Biol.Chem.273. 22913-22920 (1998)
[Publications] K.Date et al.: "Inhibition of tumor growth and invasion by a four-kringle antagonist(HGF/NK4)for hepatocyte growth fator." Oncogene. 17. 3045-3054 (1998)
[Publications] 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)
[Publications] 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)
[Publications] N.Nakano et al.: "Negative regulation of local hepatocyte growth factor(HGF)expression by angiotensin II and transforming growth factor-β in blood vessels." Hypertension. 32. 444-451 (1998)
[Publications] 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)
[Publications] 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)
[Publications] A.Jikkoet al.: "The role of hepatocyte growth factor in growth plate cartilage." J.Bone Miner.Metab.16. 170-177 (1998)
[Publications] 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)
[Publications] I.Weimar et al.: "Hepatocyte growth factor/scatter facotr(HGF/SF)affects proliferation and migration of myeloid leukemic cells." Leukemia. 12. 1195-1203 (1998)
[Publications] 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)
[Publications] S.Nakamura et al.: "Hepatocyte growth factor as a potential index of complication in diabetes mellitus." J.Hypertension. 16. 2019-2026 (1998)
[Publications] T.Ueki et al.: "Hepatocyte growth factor gene therapy of liver cirrhosis in rats" Nature Medicine. 5. 226-230 (1999)
[Publications] 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)
[Publications] M.Tahara et al.: "Hepatocyte gowth factor leads to recovery from alcohol-induced fatty liver in rats." J.Clin.Invest.103. 313-320 (1999)
[Publications] K.Matsumoto & T.Nakamura: "Hepatocyte growth factor and Met:Molecular dialogue for tissue organization and repair." Korean J.Biol.Sci.2. 1-8 (1998)
[Publications] 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)
[Publications] K.Matsumoto & T.Nakamura: "The Proceedings of the Second International Symposium of Tissue Engineering for Therapeutic Use.(in press)" Churchill Livingslone, (1998)

1998 Fiscal Year Annual Research Report

HGFによる形態形成機構の分子細胞生物学的研究

Principal Investigator

中村 敏一 大阪大学, 医学部, 教授 (00049397)

Research Products

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

[Publications] 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)

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

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

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

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

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

[Publications] 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)

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

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

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

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

[Publications] 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)

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

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

[Publications] 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)

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

[Publications] 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)

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

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

[Publications] 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)

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

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

[Publications] 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)

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

中村敏一大阪大学, 医学部, 教授 (00049397)