1999 Fiscal Year Annual Research Report

新規神経栄養因子としてのHGFファミリー因子のクローニングとその機能解析

Research Project

Project/Area Number	10680717
Research Institution	Osaka University
Principal Investigator	船越洋大阪大学, 医学系研究科, 助手 (40273685)
Co-Investigator(Kenkyū-buntansha)	中村敏一大阪大学, 医学系研究科, 教授 (00049397)
Keywords	肝細胞増殖因子 / HGF / c-Met / HLP / 神経栄養因子 / ニューロン / トランスジェニックマウス / 神経変性疾患
Research Abstract	(1) HGFとその受容体c-Metの脳神経系における発現解析 (a)大脳皮質発生過程発生過程でHGFとc-Metは部位・量共に発現制御を受けていた。培養大脳皮質ニューロンの生存,migrationと神経突起伸長活性から、HGFは大脳皮質層構造形成過程で多段階で機能していると示唆される. (b)網膜発生過程 c-Metは網膜発生過程で比較的初期から発現し、続いてHGFが発現誘導を受ける。特にc-Met/HGF受容体は成体の視細胞で発現が高く、HGFは成体視細胞において光刺激による神経細胞死の防御もしくは活動依存性の修飾に機能している可能性が示唆された。 (2) HGFのもつin vitro神経栄養活性の解析血清除去やグルタミン酸誘導性神経細胞死をHGFが濃度依存性に阻止することを培養大脳皮質・海馬ニューロンについて明らかにした。またHGFが神経細胞のmigrationを促進することをexplantと分散培養系で示した。更にアミロイドβ25-35誘導性海馬神経細胞死を阻止することを明らかとした。 (3) HGFファミリー分子(HLP)の新規神経栄養因子としての同定 HLPは比較的発生段階の進んだ鶏胚感覚経節にin vitroで神経栄養活性(神経突起伸長・migration促進活性)を示した。HLPの神経栄養活性の特異性は、Ron/HLPレセプターの細胞外ドメインとイムグロブリンFcとのキメラタンパクにより確認された。 (4) 運動神経変性疾患モデルマウスに対する新規神経栄養因子(HGF)の機能解析 (a)神経系特異的HGF発現トランスジェニックマウス(NEーHGF-Tg)の作成生後活性化される神経特異的プロモーター制御下にHGF-tagを発現する神経特異的HGF発現マウス(NS-Tg-HGF)を作成した。 (b)NS-HGF-Tgと筋萎縮性側索硬化症(ALS)モデルTg-マウスであるSOD-1変異遺伝子Tg-マウスの交配によるダブルTg-マウスの作成とHGFのALSにおける機能解析ダブルTg-マウスではHGF遺伝子を脳血液関門を考慮せず長時間ALS-Tg-マウスの神経に直接発現できる。ダアブルTg-マウスでALSの発症遅延と生存期間の解析中である。

Research Products

(37 results)

All Other

All Publications (37 results)

[Publications] W.Sun,H.Funakoshi,K.Matsumoto and T.Nakamura: "A sensitive quantification method for evaluating the level of HGF and c-met/HGF receptor mRNAs in the nervous system using competitive RT-PCR"Brain Res. Protocol. (in press). (2000)
[Publications] W.Sun,H.Funakoshi and T.Nakamura: "Differential expression of hepatocyte growth factor and its receptor, c-Met in the rat retina during development"Brain Res.. 851. 46-53 (1999)
[Publications] K.Kosai,K.Matsumoto,H.Funakoshi and T.Nakamura: "Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice"Hepatology. 30. 151-159 (1999)
[Publications] J.Wojta et al.: "Hepatocyte growth factor increases expression of vascular endothelial growth factor and plasminogen activator inhibitor-1 in human keratinocytes and the vascular endothelial growth factor receptor flk-1 in human endothelial cells. Evidence for a paracrine in wound healing"Lab. Invest. 79. 427-438 (1999)
[Publications] Z.Jiao et al.: "Effect of D-galactosamine hydrochloride and partial hepatectomy on spontaneous hepatic injury and hepatocarcinogenesis in Long Evans Cinamon rats"Jpn. J. Cancer Res.. 90. 496-504 (1999)
[Publications] H.Azuma et al.: "Effect of hepatocyte growth factor on chronic rejection in rat renal allografts"Transplat. Proc.. 31. 854-855 (1999)
[Publications] S.Takada et al.: "Effect of hepatocyte growth factor on tacrolimus-induced nephrotoxicity in spontaneously hypertensive rats"Transpl. Int.. 12. 27-32 (1999)
[Publications] H.Ueda et al.: "Gene transfection of hepatocyte growth factor attenuates reperfusion injury in the heart"Annals. Thoracic Surg.. 67. 1726-1731 (1999)
[Publications] K.Kosai,K.Matsumoto,and T.Nakamura: "Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice"Hepatology. 30. 151-159 (1999)
[Publications] R.Hasina et al.: "Autocrine and paracrine motility factors and their involvement in invasiveness in a human oral carcinoma cell line"Brit. J. Cancer. 80. 1708-1717 (1999)
[Publications] K.Kitajima,U.Koshimizu and T.Nakamura: "Expression of a novel type of classic cadherin, PB-cadherin in developing brain and limb buds"Develop. Dyn.. 215. 206-214 (1999)
[Publications] N.Taniura-Matsumoto,K.Matsumoto and T.Nakamura: "Prostaglandin production in mouse mammary carcinoma cells confers invasive growth potential by inducing hepatocyte growth factor in fibroblasts"Brit. J. Cancer. 81. 194-202 (1999)
[Publications] M.Kato,Y.Kato,T.Nakamura and Y.Sugiyama: "Efficient extraction by the liver governs the overall elimination of hepatocyte growth factor in rats"J. Phaemacol. Exp. Therap.. 290. 373-379 (1999)
[Publications] Morishita et al.: "Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as a cytokine supplement therapy"Hypertention. 33. 1379-1384 (1999)
[Publications] W.G.Jiang et al.: "Hepatocyte growth factor/scatter factor decreases the expression of occuludin and transendothelial resistance (TER) and increased paracellular permeability in human vascular endothelial cells"J. Cell. Physiol.. 181. 319-329 (1999)
[Publications] C.C.Fehlner-Gardiner et al.: "Characterization of a functional relationship between hepatocyte growth factor and mouse bone marrow-derived mast cells"Differentiation. 65. 27-42 (1999)
[Publications] S.Deleu et al.: "Immediate early gene expression in dog thyrocytes in response to growth proliferation and differentiation stimuli"J. Cell. Physiol.. 181. 342-354 (1999)
[Publications] S.Deleu et al.: "IGF-1 or insulin, and the TSH cyclic AMP cascade separately control dog and human thyroid cell growth and DNA synthesis, and complement each other in inducing mitogenesis"Mole. Cell. Endocrin.. 149. 41-51 (1999)
[Publications] S.Hayashi et al.: "Potential role of hepatocyte growth factor, a novel angiogenic growth factor in peripheral arterial disease: Downregulation of HGF in response to hypoxia in vascular cells"Circulation. 100. II-301-308 (1999)
[Publications] T.Nagahori et al.: "Interferon-gamma upregulates the c-Met/HGF receptor expression in alvedar epithelial cells"Am. J. Respir. Cell Mol. Biol.. 21. 490-497 (1999)
[Publications] O.Amano,U.Koshimizu,T.Nakamura and S.Iseki: "Enhancement by hepatocyte growth factor (HGF) of bone and cartilage formation during embryonic mouse mandibular development in vitro"Arch. Oral Biol.,. 44. 935-946 (1999)
[Publications] K.Nishimura et al.: "Prostate stromal cell-derived hepatocyte growth factor induces invasion of prostate cancer cells DU 145 through Tumor-stromal interaction"Prostate. 41. 145-153 (1999)
[Publications] T.Ueki et al.: "Hepatocyte growth factor gene therapy of liver cirrhosis in rats"Nature Medicine. 5. 226-230 (1999)
[Publications] A.Uchiyama et al.: "Hepatocyte growth factor and invasion-stimulatory activity are induced in pleural fluid by surgery in lung cancer patients"Br. J. Cancer. 81. 721-726 (1999)
[Publications] K.Matsumoto et al.: "Prevention of renal damage by Angiotensin II blockade, accompanied by increased renal hepatocyte growth factor in experimental hypertensive rats"Hypertension. 34. 279-284 (1999)
[Publications] Y.Okura et al.: "Analysis of neurotrophic factor of hepatocyte growth factor (HGF) in the adult hypoglossal nerve axotomy model"Eur J. Neurosci.. 11. 4139-4144 (1999)
[Publications] T.Sumi,K.Matsumoto,Y.Takai and T.Nakamura: "Cofilin phosphorylation and actin cytoskeletal dynamics regulated by Rho- and Cdc42-activated LIM-kinase 2"J. Cell Biol.. 147. 1519-1532 (1999)
[Publications] M.K.Jones et al.: "HGF triggers activation of Cox-2 gene in rat gastric epithelial cells Action mediated through the ERK2 signalling pathway"FASEB J.. 13. 2186-2194 (1999)
[Publications] Y.Kawano et al.: "Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase by Rho-kinase in vivo"J. Cell Biol.. 147. 1023-1037 (1999)
[Publications] F.Tamura et al.: "FK506 promotes liver regeneration by suppressing natural killer cell activity"J. Gastroenterol. and Hepatol. (in press). (2000)
[Publications] A.Uchiyama et al.: "Significance of locally-secreted hepatocyte growth factor after thoracic cancer surgery as a stimulator for postoperative cancer invasion"Jpn. J. Clin. Oncol.. (in press). (2000)
[Publications] W.G.Jiang et al.: "Antagonistic effect of NK4, a novel HGF variant, on in vitro angiogenesis of human vascular endothelial cells"Clin. Cancer Res.. (in press). (2000)
[Publications] S.Hiscox et al.: "Inhibition of HGF/SF-induced breast cancer cell matility and invasion by the HGF/SF variant, NK4"Breast Cancer Res. & Treat.. (in press). (2000)
[Publications] M.Nakano et al.: "Hepatocyte growth factor is essential for amelioration of hyperglycemia in strepto zotocin-induced diabetic mice receiving a marginal mass of intrahepatic islet grafts"Transplantation. (in press). (2000)
[Publications] T.Yamada et al.: "Enhanced expression of hepatocyte growth factor by pulmonary ischemia reperfusion injury in the rat"Am. J. Resp. Crit Care Med.. (in press). (2000)
[Publications] 船越洋、中村敏一: "肝細胞増殖因子因子 (HGF) の検査値と各種疾患"日本臨床. 57. 821-826 (1999)
[Publications] 船越洋、紀氏 A.優子、中村敏一: "キメラタンパク作成法と利用"脳の科学. 21. 537-542 (1999)

1999 Fiscal Year Annual Research Report

新規神経栄養因子としてのHGFファミリー因子のクローニングとその機能解析

Principal Investigator

船越 洋 大阪大学, 医学系研究科, 助手 (40273685)

Research Products

[Publications] W.Sun,H.Funakoshi,K.Matsumoto and T.Nakamura: "A sensitive quantification method for evaluating the level of HGF and c-met/HGF receptor mRNAs in the nervous system using competitive RT-PCR"Brain Res. Protocol. (in press). (2000)

[Publications] W.Sun,H.Funakoshi and T.Nakamura: "Differential expression of hepatocyte growth factor and its receptor, c-Met in the rat retina during development"Brain Res.. 851. 46-53 (1999)

[Publications] K.Kosai,K.Matsumoto,H.Funakoshi and T.Nakamura: "Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice"Hepatology. 30. 151-159 (1999)

[Publications] Z.Jiao et al.: "Effect of D-galactosamine hydrochloride and partial hepatectomy on spontaneous hepatic injury and hepatocarcinogenesis in Long Evans Cinamon rats"Jpn. J. Cancer Res.. 90. 496-504 (1999)

[Publications] H.Azuma et al.: "Effect of hepatocyte growth factor on chronic rejection in rat renal allografts"Transplat. Proc.. 31. 854-855 (1999)

[Publications] S.Takada et al.: "Effect of hepatocyte growth factor on tacrolimus-induced nephrotoxicity in spontaneously hypertensive rats"Transpl. Int.. 12. 27-32 (1999)

[Publications] H.Ueda et al.: "Gene transfection of hepatocyte growth factor attenuates reperfusion injury in the heart"Annals. Thoracic Surg.. 67. 1726-1731 (1999)

[Publications] K.Kosai,K.Matsumoto,and T.Nakamura: "Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice"Hepatology. 30. 151-159 (1999)

[Publications] R.Hasina et al.: "Autocrine and paracrine motility factors and their involvement in invasiveness in a human oral carcinoma cell line"Brit. J. Cancer. 80. 1708-1717 (1999)

[Publications] K.Kitajima,U.Koshimizu and T.Nakamura: "Expression of a novel type of classic cadherin, PB-cadherin in developing brain and limb buds"Develop. Dyn.. 215. 206-214 (1999)

[Publications] N.Taniura-Matsumoto,K.Matsumoto and T.Nakamura: "Prostaglandin production in mouse mammary carcinoma cells confers invasive growth potential by inducing hepatocyte growth factor in fibroblasts"Brit. J. Cancer. 81. 194-202 (1999)

[Publications] M.Kato,Y.Kato,T.Nakamura and Y.Sugiyama: "Efficient extraction by the liver governs the overall elimination of hepatocyte growth factor in rats"J. Phaemacol. Exp. Therap.. 290. 373-379 (1999)

[Publications] Morishita et al.: "Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as a cytokine supplement therapy"Hypertention. 33. 1379-1384 (1999)

[Publications] W.G.Jiang et al.: "Hepatocyte growth factor/scatter factor decreases the expression of occuludin and transendothelial resistance (TER) and increased paracellular permeability in human vascular endothelial cells"J. Cell. Physiol.. 181. 319-329 (1999)

[Publications] C.C.Fehlner-Gardiner et al.: "Characterization of a functional relationship between hepatocyte growth factor and mouse bone marrow-derived mast cells"Differentiation. 65. 27-42 (1999)

[Publications] S.Deleu et al.: "Immediate early gene expression in dog thyrocytes in response to growth proliferation and differentiation stimuli"J. Cell. Physiol.. 181. 342-354 (1999)

[Publications] S.Deleu et al.: "IGF-1 or insulin, and the TSH cyclic AMP cascade separately control dog and human thyroid cell growth and DNA synthesis, and complement each other in inducing mitogenesis"Mole. Cell. Endocrin.. 149. 41-51 (1999)

[Publications] S.Hayashi et al.: "Potential role of hepatocyte growth factor, a novel angiogenic growth factor in peripheral arterial disease: Downregulation of HGF in response to hypoxia in vascular cells"Circulation. 100. II-301-308 (1999)

[Publications] T.Nagahori et al.: "Interferon-gamma upregulates the c-Met/HGF receptor expression in alvedar epithelial cells"Am. J. Respir. Cell Mol. Biol.. 21. 490-497 (1999)

[Publications] O.Amano,U.Koshimizu,T.Nakamura and S.Iseki: "Enhancement by hepatocyte growth factor (HGF) of bone and cartilage formation during embryonic mouse mandibular development in vitro"Arch. Oral Biol.,. 44. 935-946 (1999)

[Publications] K.Nishimura et al.: "Prostate stromal cell-derived hepatocyte growth factor induces invasion of prostate cancer cells DU 145 through Tumor-stromal interaction"Prostate. 41. 145-153 (1999)

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

[Publications] A.Uchiyama et al.: "Hepatocyte growth factor and invasion-stimulatory activity are induced in pleural fluid by surgery in lung cancer patients"Br. J. Cancer. 81. 721-726 (1999)

[Publications] K.Matsumoto et al.: "Prevention of renal damage by Angiotensin II blockade, accompanied by increased renal hepatocyte growth factor in experimental hypertensive rats"Hypertension. 34. 279-284 (1999)

[Publications] Y.Okura et al.: "Analysis of neurotrophic factor of hepatocyte growth factor (HGF) in the adult hypoglossal nerve axotomy model"Eur J. Neurosci.. 11. 4139-4144 (1999)

[Publications] T.Sumi,K.Matsumoto,Y.Takai and T.Nakamura: "Cofilin phosphorylation and actin cytoskeletal dynamics regulated by Rho- and Cdc42-activated LIM-kinase 2"J. Cell Biol.. 147. 1519-1532 (1999)

[Publications] M.K.Jones et al.: "HGF triggers activation of Cox-2 gene in rat gastric epithelial cells Action mediated through the ERK2 signalling pathway"FASEB J.. 13. 2186-2194 (1999)

[Publications] Y.Kawano et al.: "Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase by Rho-kinase in vivo"J. Cell Biol.. 147. 1023-1037 (1999)

[Publications] F.Tamura et al.: "FK506 promotes liver regeneration by suppressing natural killer cell activity"J. Gastroenterol. and Hepatol. (in press). (2000)

[Publications] A.Uchiyama et al.: "Significance of locally-secreted hepatocyte growth factor after thoracic cancer surgery as a stimulator for postoperative cancer invasion"Jpn. J. Clin. Oncol.. (in press). (2000)

[Publications] W.G.Jiang et al.: "Antagonistic effect of NK4, a novel HGF variant, on in vitro angiogenesis of human vascular endothelial cells"Clin. Cancer Res.. (in press). (2000)

[Publications] S.Hiscox et al.: "Inhibition of HGF/SF-induced breast cancer cell matility and invasion by the HGF/SF variant, NK4"Breast Cancer Res. & Treat.. (in press). (2000)

[Publications] M.Nakano et al.: "Hepatocyte growth factor is essential for amelioration of hyperglycemia in strepto zotocin-induced diabetic mice receiving a marginal mass of intrahepatic islet grafts"Transplantation. (in press). (2000)

[Publications] T.Yamada et al.: "Enhanced expression of hepatocyte growth factor by pulmonary ischemia reperfusion injury in the rat"Am. J. Resp. Crit Care Med.. (in press). (2000)

[Publications] 船越 洋、中村 敏一: "肝細胞増殖因子因子 (HGF) の検査値と各種疾患"日本臨床. 57. 821-826 (1999)

[Publications] 船越 洋、紀氏 A.優子、中村 敏一: "キメラタンパク作成法と利用"脳の科学. 21. 537-542 (1999)

船越洋大阪大学, 医学系研究科, 助手 (40273685)

[Publications] 船越洋、中村敏一: "肝細胞増殖因子因子 (HGF) の検査値と各種疾患"日本臨床. 57. 821-826 (1999)

[Publications] 船越洋、紀氏 A.優子、中村敏一: "キメラタンパク作成法と利用"脳の科学. 21. 537-542 (1999)