1999 年度実績報告書

難治性臓器疾患に対するHGP(肝細胞増殖因子)の抗線維化の解析と治療への応用

研究課題

研究課題/領域番号	11557010
研究種目	基盤研究(B)
研究機関	大阪大学
研究代表者	松本邦夫大阪大学, 医学系研究科, 助教授 (90201780)
研究分担者	船越洋大阪大学, 医学系研究科, 助手 (40273685) 小清水右一大阪大学, 医学系研究科, 助手 (50281126)
キーワード	肝細胞増殖因子 / HGF / 組織再生 / 組織線維化 / 難治性臓器疾患 / 再生医学 / 病理発生 / 遺伝子治療
研究概要	慢性腎不全や肝硬変は組織線維化によって特徴づけられ、移植以外に根本的な救命法がない難治性疾患とされてきた。一方、肝再生因子として見出されたHGFは組織修復に重要な因子であることがわかってきた。そこで本年度は慢性腎不全および肝硬変の病理発生におけるHGFの内因性修復因子としての機能をモデル動物を用いて検証した。 1.慢性腎不全におけるHGFの内因性修復因子としての重要性. 慢性腎不全を自然発症するICGNマウスを用いて腎線維化の病理発生におけるHGF発現の意義を解析した。慢性腎不全の初期では間質線維芽細胞にHGFが強く発現しており、これに一致して尿細管再生が観察され、腎機能も維持されていた。そこでこの代償期にHGFの中和抗体を投与してみたところ、尿細管にアポトーシスが誘導され、これに一致して線維化誘導因子であるTGF-βの。発現が誘導された。その結果、尿細管間質に線維形成が加速され、腎機能も著しい低下を示した。一方、このマウスにリコンビナントHGFを投与すると、尿細管に再生が駆動されるとともに腎機能も正常値にまで改善された。 2.肝硬変におけるHGF遺伝子導入による病理発生機構の解析代表的な肝臓毒であるDMNを用いて作成したラットの肝硬変においてその進行に一致して内因性HGFの枯渇が観察された。そこでHVJ-リポソーム法によりHGF遺伝子を生体内に導入したところ、HGFレベルの上昇に伴って肝細胞は再生し、TGF-βの発現の発現抑制制とともに肝硬変の病態も強く改善された。以上の事から、腎臓や肝臓の組織線維化は内因性HGFの枯渇によって加速されている一方、外来性HGFが治療因子となり得る可能性が示唆された。

研究成果

(31件)

すべてその他

すべて文献書誌 (31件)

[文献書誌] T.Urki,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,K.Matsumoto,T.Nukiwa,and T.Nakamura.: "Hepatocyte growth factor leads to recovery from alcohol-induced fatty liver in rats"J.Clin.Invest. 103. 313-320 (1999)
[文献書誌] H.Azuma,et al.: "Effect of hepatocyte growth factor on chronic rejection in rat renal allografts"Transplat.Proc.. 31. 854-855 (1999)
[文献書誌] S.Takada,et al.: "Effect of hepatocyte growth factor on tacrolimus-induced nephrotoxicity in spontaneously hypertensive rats"Transpl.Int.. 12. 27-32 (1999)
[文献書誌] H.Ueda,et al.: "Gene transfection of hepatocyte growth factor attenuates reperfusion injury in the heart"Annals.Thoracic Surg.. 67. 1726-1731 (1999)
[文献書誌] K.Kosai,K.Matsumoto,and T.Nakamura: "Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice"Hepatology. 30. 151-159 (1999)
[文献書誌] 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)
[文献書誌] 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)
[文献書誌] Morishita,et al.: "Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as a cytokine supplement therapy"Hypertension. 33. 1379-1384 (1999)
[文献書誌] 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 cells."J.Cell.Physiol.. 181. 319-329 (1999)
[文献書誌] 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-II308 (1999)
[文献書誌] T.Nagahori,et al.: "Interferon-gamma upregulates the c-Met/HGF receptor expression in alveolar epithelial cells"Am.J.Reapir.Cell Mol. Biol.. 21. 490-497 (1999)
[文献書誌] K.Nishimura,et al.: "Prostate stromal cell-derived hepatocyte growth factor induces invasion of prostate cancer cells DU 145 through Tumor-stromal interraction"Prostate. 41. 145-153 (1999)
[文献書誌] W.Sun,H.Funakoshi and T.Nakamura: "Differential expression of hepatocyte growth factor and receptor, c-Met in the rat retina during development"Brain Res.. 851. 46-53 (1999)
[文献書誌] 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)
[文献書誌] 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)
[文献書誌] 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)
[文献書誌] T.Sumi,K.Matsumoto,Y.Takai and T.Nakamura: "Cofilin phosphorylation and cytoskeletal dynamics regulated by Rho-and Cdc42-activated LIM-kinase2"J.Cell Biol.. 147. 1519-1532 (1999)
[文献書誌] 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)
[文献書誌] 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)
[文献書誌] 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)
[文献書誌] 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)
[文献書誌] S.Mizuno,et al.: "Reciprocal balance between HGF and TGF-β a key determinant for pathological phenotypes in chronic renal disease"Kidney Intern.. (in press). (2000)
[文献書誌] 久場敬司、松本邦夫、中村俊一: "HGFによる血管新生とその分子内クリングル断片(NK4)による腫瘍血管新生阻害"実験医学. 17. 734-740 (1999)
[文献書誌] 松本邦夫、中村敏一: "HGFの臨床応用に向けて"Medical Academy News. 720/721. 12-12 (1999)
[文献書誌] 松本邦夫、中村敏一: "肝細胞の培養法"細胞生物学実験法. 1. 27-47 (1999)
[文献書誌] 松本邦夫、中村敏一: "タンパク質の分析法"分子生物学プロトコール改訂2版. 11章. 269-284 (1999)
[文献書誌] 松本邦夫: "HGFによる再生医学の実践"実験医学. 18. 424-430 (2000)
[文献書誌] 松本邦夫、中村敏一: "HGFの分析内断片NK4による血管新生阻害と制癌"Molecular Medicine. 37. 276-282 (2000)
[文献書誌] 松本邦夫、中村敏一: "HGFの分子内断片NK4による血管新生阻害と制癌"Molecular Medicine. 37. 276-282 (2000)

1999 年度 実績報告書

難治性臓器疾患に対するHGP(肝細胞増殖因子)の抗線維化の解析と治療への応用

研究代表者

松本 邦夫 大阪大学, 医学系研究科, 助教授 (90201780)

研究成果

[文献書誌] T.Urki,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,K.Matsumoto,T.Nukiwa,and T.Nakamura.: "Hepatocyte growth factor leads to recovery from alcohol-induced fatty liver in rats"J.Clin.Invest. 103. 313-320 (1999)

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

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

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

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

[文献書誌] 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)

[文献書誌] 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)

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

[文献書誌] 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 cells."J.Cell.Physiol.. 181. 319-329 (1999)

[文献書誌] 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-II308 (1999)

[文献書誌] T.Nagahori,et al.: "Interferon-gamma upregulates the c-Met/HGF receptor expression in alveolar epithelial cells"Am.J.Reapir.Cell Mol. Biol.. 21. 490-497 (1999)

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

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

[文献書誌] 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)

[文献書誌] 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)

[文献書誌] 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)

[文献書誌] T.Sumi,K.Matsumoto,Y.Takai and T.Nakamura: "Cofilin phosphorylation and cytoskeletal dynamics regulated by Rho-and Cdc42-activated LIM-kinase2"J.Cell Biol.. 147. 1519-1532 (1999)

[文献書誌] 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)

[文献書誌] 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)

[文献書誌] 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)

[文献書誌] 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)

[文献書誌] S.Mizuno,et al.: "Reciprocal balance between HGF and TGF-β a key determinant for pathological phenotypes in chronic renal disease"Kidney Intern.. (in press). (2000)

[文献書誌] 久場敬司、松本邦夫、中村俊一: "HGFによる血管新生とその分子内クリングル断片(NK4)による腫瘍血管新生阻害"実験医学. 17. 734-740 (1999)

[文献書誌] 松本邦夫、中村敏一: "HGFの臨床応用に向けて"Medical Academy News. 720/721. 12-12 (1999)

[文献書誌] 松本邦夫、中村敏一: "肝細胞の培養法"細胞生物学実験法. 1. 27-47 (1999)

[文献書誌] 松本邦夫、中村敏一: "タンパク質の分析法"分子生物学プロトコール 改訂2版. 11章. 269-284 (1999)

[文献書誌] 松本邦夫: "HGFによる再生医学の実践"実験医学. 18. 424-430 (2000)

[文献書誌] 松本邦夫、中村敏一: "HGFの分析内断片NK4による血管新生阻害と制癌"Molecular Medicine. 37. 276-282 (2000)

[文献書誌] 松本邦夫、中村敏一: "HGFの分子内断片NK4による血管新生阻害と制癌"Molecular Medicine. 37. 276-282 (2000)

1999 年度実績報告書

松本邦夫大阪大学, 医学系研究科, 助教授 (90201780)

[文献書誌] 松本邦夫、中村敏一: "タンパク質の分析法"分子生物学プロトコール改訂2版. 11章. 269-284 (1999)