2002 年度実績報告書

器官修復システムの破綻による組織線維化機構の分子基盤

研究課題

研究課題/領域番号	14207005
研究種目	基盤研究(A)
研究機関	大阪大学
研究代表者	中村敏一大阪大学, 医学系研究科, 教授 (00049397)
研究分担者	水野信哉大阪大学, 医学系研究科, 助手 (10219644) 船越洋大阪大学, 医学系研究科, 助教授 (40273685) 松本邦夫大阪大学, 医学系研究科, 助教授 (90201780)
キーワード	組織線維化 / HGF / 慢性疾患 / 筋線維芽細胞 / 細胞外マトリックス / TGF-β / 組織再生 / 再生医学
研究概要	肝硬変や慢性腎不全などの慢性疾患では実質組織の破綻とともに間質での細胞外マトリックス過剰蓄積に特徴付けられる組織線維症が進行する。このような線維化の過程にで間質における筋線維芽細胞の過剰蓄積が共通の病理発生機序として注目されている。一方、私達はHGFが肝硬変などの慢性疾患において上皮の再生を駆動して組織線維化の進展を阻止することを明らかにして来たが、間質に対するHGFの直接的な機能については不明であった。そこで本年度は筋線維芽細胞におけるHGFの機能解析に着手したところ、現在までに以下の研究成果を得るに至った。 1)慢性腎不全/糸球体腎炎のラットモデルを用いて、HGFが腎メサンギウム細胞由来の筋線維芽細胞に対してその増殖を制御することを明らかにした。この作用点を明らかにすべく培養メサンギウム細胞を用いて解析したところ、HGFはPDGFが誘導するMAPキナーゼ系の活性化を制御し、サイクリンD1の発現を抑制することで過剰増殖を制御していることが判明した。以上の結果は肝硬変のモデルでも同様に再現しており、HGFは筋線維芽細胞の増殖抑制と上皮再生の両方の機能を発揮して強力な抗線維化効果を発揮していると予想される。 2)拡張型心筋症のハムスターモデルを用いてHGFが心筋線維化を制御するとともに心筋収縮能を改善する機能を持つことを明らかにした。心筋組織でも筋線維芽細胞はHGF受容体/c-Metを発現していた。そこで心由来の筋線維芽細胞の培養系を用いてHGFの生理的機能を解析したところ、HGFはこの細胞に直接作用して繊維化誘導因子であるTGF-βの産生を抑制すること、さらにコラーゲンなどの細胞外基質の産生を阻止する作用を有することが明らかとなった。

研究成果

(45件)

すべてその他

すべて文献書誌 (45件)

[文献書誌] K.Bessho, et al.: "Counteractive effects of HGF on PDGF-mediated mesangial cell proliferation in a rat model of glomerulonephritis"Am.J.Physiol.. (In press). (2003)
[文献書誌] H.Funakoshi, et al.: "Hepatocyte growth factor : from diagnosis to clinical applications"Clin Chim Acta. 327. 1-23 (2003)
[文献書誌] S.Yoshida, et al.: "Neutralization of hepatocyte growth factor leads to retarded cutaneous wound healing associated with decreased neovascularization and granulation tissue formation"J.Dermatol.Invest.. 120. 335-343 (2003)
[文献書誌] T.Inoue, et al.: "HGF counteracts transforming growth factor-β1, through attenuation of connective growth factor induction, and prevents renal fibrogenesis in 5/6-nephrectomized mice"FASEB J. 17. 268-280 (2003)
[文献書誌] K.Matsumoto, et al.: "Renotropic role and therapeutic potential of HGF in the kidney"Nephrol.Dial.Transplant.. 17. 59-61 (2003)
[文献書誌] W.Sun: "Overexpression of HGF retards disease progression and prolongs life span in a transgenic mouse model of ALS"J.Neurosci.. 22. 6537-6548 (2002)
[文献書誌] Y.Sakamaki, et al.: "Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during ostpneumonectomy compenbatory lung growth in mice"Am.J.Respir.Cell Mol.Biol.. 26. 525-533 (2002)
[文献書誌] H.Takahashi, et al.: "Impaired spermatogenic ability of testicular germ cells in mice dificient in the LIM-kinase 2 gene"Develop.Biol.. 241. 259-272 (2002)
[文献書誌] H.Funakoshi, et al.: "Identification of Gas 6, a putative ligand for Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons"J.Neursci.Res.. 68. 150-160 (2002)
[文献書誌] T.Sumi, et al.: "Mitosis-dependent phosphorylation and activation of LIM-kinase 1"Biochem.Biophys.Res.Commun.. 290. 1315-1320 (2002)
[文献書誌] Y.A.Kishi, et al.: "Xksy, a gene expressed in developing neural tissues, encodes a novel Sky family receptor tyrosine kinase with a glutamic acid-rich domain"Gene. 288. 29-40 (2002)
[文献書誌] W.Sun, et al.: "Localization and functional role of hepatocyte growth factor(HGF) and its receptor c-Met in the rat developing cerebral cortex"Mol.Brain Res.. 103. 36-48 (2002)
[文献書誌] H.Shibuki, et al.: "Expression and neuroprotective effect of hepatocyte growth factor in retinal ischemic-reperfusion injury"Invest.Ophthalmol.Vis.Sci.. 43. 528-536 (2002)
[文献書誌] M.Maemondo, et al.: "Targeting angiogenesis and HGF function by an adenoviral vector expressing HGF antagonist, NK4 for cancer therapy"Mol.Therapy. 5. 177-185 (2002)
[文献書誌] S.Hirao, et al.: "Tumor suppression effect using NK4, novel moleculeacting as the antagonist of HGF, on human gastric caranomas"Cancer Gene Therapy. 9. 700-707 (2002)
[文献書誌] M.Saimura, et al.: "Intraperitoneal injection of adenovirus-mediated NK4 gene suppresses peritoneal dissemination of pancreatic cancer cell line AsPC-1 in nude mice"Cancer Gene Therapy. 9. 799-806 (2002)
[文献書誌] R.Morishita, et al.: "Impairment of collateral formation in lepoprotein(a)transgenic mice : Therapeutic angiogenesis induced by human hepatocyte growth factor gene"Circulation. 105. 1491-1496 (2002)
[文献書誌] S.Miyagawa, et al.: "Myocardial regeneration therapy for heart failure : Hepatocyte growth factor enhances the effect of cellular cardiomyoplasty"Circulation. 105. 2556-2561 (2002)
[文献書誌] T.Tanaka, et al.: "In vivo gene transfer of hepatocyte growth factor to skeletal muscle prevents changes in rat kidney after 5/6 nephrectomy"Am.J.Transplant.. 2. 828-836 (2002)
[文献書誌] M.Ono, et al.: "In vivo gene transfection with hepatocyte growth factor via pulmonary artery induces angiogenesis in the rat lung"Circulation. 106. I-264-I-269 (2002)
[文献書誌] H.Nakagami, et al.: "Hepatocyte growth factor prevents endothelial cell death through inhibition of bax translocation from cytosol mitochondrial membrane"Diabetes. 51. 2604-2611 (2002)
[文献書誌] O.Amano, et al.: "Hepatocyte growth factor is essential for migration of myogenic cells and promotes their proliferation during the early periods of tongue morphorogenesis in mouse embryos"Developmental Dyn.. 223. 169-179 (2002)
[文献書誌] T.Sugimoto, et al.: "Decreased microsomal triglyceride transfer protein activity contributes to inhibition of alcoholic liver steatosis in rats"J.Hepatol.. 84. 864-873 (2002)
[文献書誌] T.Funatsu, et al.: "Therapeutic angiogenesis induced by myocardial injection of nacked cDNA plasmid encoding hepatocyte growth factor in ischemic canine heart"Cardiovas.Res. 12. 1280-1292 (2002)
[文献書誌] Y.Taniyama, et al.: "Development of safe and efficient novel non-viral gene transfer using ultrasound : enhancement of transfection efficiency of naked plasmid DNA in skeletal muscle"Gene Therapy. 9. 372-380 (2002)
[文献書誌] H.Miura, et al.: "Effect of hepatocyte growth factor on E-cadherin-mediated cell-cell adhesion in DU 145 prostate cancer cells"Urology. 61. 7518-7524 (2002)
[文献書誌] M.Saimura, et al.: "Tumor suppression through angiogenesis inhibition by Suit-2 pancreatic cancer cells genetically engineered to secrete NK4"Clin.Cancer Res. 8. 3243-3249 (2002)
[文献書誌] N.Maehara, et al.: "Gene transduction of NK4, HGF antagonist, inhibits in vivo invasion and in vivo growth of human pancreatic cancer"Clin.& Exp.Metastasis. 19. 417-426 (2002)
[文献書誌] S.Hirano, et al.: "Tumor suppression effect using NK4, novel moleculeacting as the antagonist of HGF, on human gastric caranomas"Cancer Gene Therapy. 9. 700-707 (2002)
[文献書誌] K.Nakanishi, et al.: "Gene transfer of human HGF into rat skin wounds mediated by liposomes coated with the Sendai virus (Hemagglutinating virus of Japan)"Am.J.Pathol.. 161. 1761-1772 (2002)
[文献書誌] Y.Taniyama, et al.: "Angiogenesis and antifibrotic action by hepatocyte growth factor in cardiomyopathy"Hypertension. 40. 47-53 (2002)
[文献書誌] C.Paneda, et al.: "Liver cell proliferation requires methionine adenosyltransferase 2A mRNA up-regualtion"Hepatology. 35. 1381-1391 (2002)
[文献書誌] Y.To, et al.: "A two way interaction between hepatocyte growth factor and interleukin-6 on tissul invasion of lung cancer cell line"Am.J.Respir.Cell Mol.Biol.. 27. 220-226 (2002)
[文献書誌] K.Matsumoto, et al.: "Impaired endothelial dysfunction in diabetes mellitus rats was restored by oral administaration of prostaglandin I2 analogue]"J.Endocrinol.. 175. 217-223 (2002)
[文献書誌] 水野信哉, 他: "The Lung Perspective"メディカルレビュー社(印刷中). (2003)
[文献書誌] 水野信哉, 他: "臨床免疫2003"科学論評社(印刷中). (2003)
[文献書誌] 福田一弘, 他: "遺伝子医学別"メディカルドゥ(印刷中). (2003)
[文献書誌] 水野信哉, 他: "再生医学・再生医療"東京化学同人. 12 (2002)
[文献書誌] 水野信哉, 他: "Annual Review 腎臓"中外医学社. 11 (2002)
[文献書誌] 別所一彦, 他: "遺伝子医学"メディカルドゥ. 7 (2002)
[文献書誌] 別所一彦, 他: "実験医学増刊"羊土社. 9 (2002)
[文献書誌] 角智行, 他: "生化学"日本生化学学会. 6 (2002)
[文献書誌] 松本邦夫, 他: "日経サイエンス"日本経済新聞社. 12 (2002)
[文献書誌] 坂巻靖, 他: "The Lung Perspective"メディカルレビュー社. 8 (2002)
[文献書誌] 久場敬司, 他: "実験医学増刊"羊土社. 8 (2002)

2002 年度 実績報告書

器官修復システムの破綻による組織線維化機構の分子基盤

研究代表者

中村 敏一 大阪大学, 医学系研究科, 教授 (00049397)

研究成果

[文献書誌] K.Bessho, et al.: "Counteractive effects of HGF on PDGF-mediated mesangial cell proliferation in a rat model of glomerulonephritis"Am.J.Physiol.. (In press). (2003)

[文献書誌] H.Funakoshi, et al.: "Hepatocyte growth factor : from diagnosis to clinical applications"Clin Chim Acta. 327. 1-23 (2003)

[文献書誌] S.Yoshida, et al.: "Neutralization of hepatocyte growth factor leads to retarded cutaneous wound healing associated with decreased neovascularization and granulation tissue formation"J.Dermatol.Invest.. 120. 335-343 (2003)

[文献書誌] T.Inoue, et al.: "HGF counteracts transforming growth factor-β1, through attenuation of connective growth factor induction, and prevents renal fibrogenesis in 5/6-nephrectomized mice"FASEB J. 17. 268-280 (2003)

[文献書誌] K.Matsumoto, et al.: "Renotropic role and therapeutic potential of HGF in the kidney"Nephrol.Dial.Transplant.. 17. 59-61 (2003)

[文献書誌] W.Sun: "Overexpression of HGF retards disease progression and prolongs life span in a transgenic mouse model of ALS"J.Neurosci.. 22. 6537-6548 (2002)

[文献書誌] Y.Sakamaki, et al.: "Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during ostpneumonectomy compenbatory lung growth in mice"Am.J.Respir.Cell Mol.Biol.. 26. 525-533 (2002)

[文献書誌] H.Takahashi, et al.: "Impaired spermatogenic ability of testicular germ cells in mice dificient in the LIM-kinase 2 gene"Develop.Biol.. 241. 259-272 (2002)

[文献書誌] H.Funakoshi, et al.: "Identification of Gas 6, a putative ligand for Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons"J.Neursci.Res.. 68. 150-160 (2002)

[文献書誌] T.Sumi, et al.: "Mitosis-dependent phosphorylation and activation of LIM-kinase 1"Biochem.Biophys.Res.Commun.. 290. 1315-1320 (2002)

[文献書誌] Y.A.Kishi, et al.: "Xksy, a gene expressed in developing neural tissues, encodes a novel Sky family receptor tyrosine kinase with a glutamic acid-rich domain"Gene. 288. 29-40 (2002)

[文献書誌] W.Sun, et al.: "Localization and functional role of hepatocyte growth factor(HGF) and its receptor c-Met in the rat developing cerebral cortex"Mol.Brain Res.. 103. 36-48 (2002)

[文献書誌] H.Shibuki, et al.: "Expression and neuroprotective effect of hepatocyte growth factor in retinal ischemic-reperfusion injury"Invest.Ophthalmol.Vis.Sci.. 43. 528-536 (2002)

[文献書誌] M.Maemondo, et al.: "Targeting angiogenesis and HGF function by an adenoviral vector expressing HGF antagonist, NK4 for cancer therapy"Mol.Therapy. 5. 177-185 (2002)

[文献書誌] S.Hirao, et al.: "Tumor suppression effect using NK4, novel moleculeacting as the antagonist of HGF, on human gastric caranomas"Cancer Gene Therapy. 9. 700-707 (2002)

[文献書誌] M.Saimura, et al.: "Intraperitoneal injection of adenovirus-mediated NK4 gene suppresses peritoneal dissemination of pancreatic cancer cell line AsPC-1 in nude mice"Cancer Gene Therapy. 9. 799-806 (2002)

[文献書誌] R.Morishita, et al.: "Impairment of collateral formation in lepoprotein(a)transgenic mice : Therapeutic angiogenesis induced by human hepatocyte growth factor gene"Circulation. 105. 1491-1496 (2002)

[文献書誌] S.Miyagawa, et al.: "Myocardial regeneration therapy for heart failure : Hepatocyte growth factor enhances the effect of cellular cardiomyoplasty"Circulation. 105. 2556-2561 (2002)

[文献書誌] T.Tanaka, et al.: "In vivo gene transfer of hepatocyte growth factor to skeletal muscle prevents changes in rat kidney after 5/6 nephrectomy"Am.J.Transplant.. 2. 828-836 (2002)

[文献書誌] M.Ono, et al.: "In vivo gene transfection with hepatocyte growth factor via pulmonary artery induces angiogenesis in the rat lung"Circulation. 106. I-264-I-269 (2002)

[文献書誌] H.Nakagami, et al.: "Hepatocyte growth factor prevents endothelial cell death through inhibition of bax translocation from cytosol mitochondrial membrane"Diabetes. 51. 2604-2611 (2002)

[文献書誌] O.Amano, et al.: "Hepatocyte growth factor is essential for migration of myogenic cells and promotes their proliferation during the early periods of tongue morphorogenesis in mouse embryos"Developmental Dyn.. 223. 169-179 (2002)

[文献書誌] T.Sugimoto, et al.: "Decreased microsomal triglyceride transfer protein activity contributes to inhibition of alcoholic liver steatosis in rats"J.Hepatol.. 84. 864-873 (2002)

[文献書誌] T.Funatsu, et al.: "Therapeutic angiogenesis induced by myocardial injection of nacked cDNA plasmid encoding hepatocyte growth factor in ischemic canine heart"Cardiovas.Res. 12. 1280-1292 (2002)

[文献書誌] Y.Taniyama, et al.: "Development of safe and efficient novel non-viral gene transfer using ultrasound : enhancement of transfection efficiency of naked plasmid DNA in skeletal muscle"Gene Therapy. 9. 372-380 (2002)

[文献書誌] H.Miura, et al.: "Effect of hepatocyte growth factor on E-cadherin-mediated cell-cell adhesion in DU 145 prostate cancer cells"Urology. 61. 7518-7524 (2002)

[文献書誌] M.Saimura, et al.: "Tumor suppression through angiogenesis inhibition by Suit-2 pancreatic cancer cells genetically engineered to secrete NK4"Clin.Cancer Res. 8. 3243-3249 (2002)

[文献書誌] N.Maehara, et al.: "Gene transduction of NK4, HGF antagonist, inhibits in vivo invasion and in vivo growth of human pancreatic cancer"Clin.& Exp.Metastasis. 19. 417-426 (2002)

[文献書誌] S.Hirano, et al.: "Tumor suppression effect using NK4, novel moleculeacting as the antagonist of HGF, on human gastric caranomas"Cancer Gene Therapy. 9. 700-707 (2002)

[文献書誌] K.Nakanishi, et al.: "Gene transfer of human HGF into rat skin wounds mediated by liposomes coated with the Sendai virus (Hemagglutinating virus of Japan)"Am.J.Pathol.. 161. 1761-1772 (2002)

[文献書誌] Y.Taniyama, et al.: "Angiogenesis and antifibrotic action by hepatocyte growth factor in cardiomyopathy"Hypertension. 40. 47-53 (2002)

[文献書誌] C.Paneda, et al.: "Liver cell proliferation requires methionine adenosyltransferase 2A mRNA up-regualtion"Hepatology. 35. 1381-1391 (2002)

[文献書誌] Y.To, et al.: "A two way interaction between hepatocyte growth factor and interleukin-6 on tissul invasion of lung cancer cell line"Am.J.Respir.Cell Mol.Biol.. 27. 220-226 (2002)

[文献書誌] K.Matsumoto, et al.: "Impaired endothelial dysfunction in diabetes mellitus rats was restored by oral administaration of prostaglandin I2 analogue]"J.Endocrinol.. 175. 217-223 (2002)

[文献書誌] 水野信哉, 他: "The Lung Perspective"メディカルレビュー社(印刷中). (2003)

[文献書誌] 水野信哉, 他: "臨床免疫2003"科学論評社(印刷中). (2003)

[文献書誌] 福田一弘, 他: "遺伝子医学別"メディカルドゥ(印刷中). (2003)

[文献書誌] 水野信哉, 他: "再生医学・再生医療"東京化学同人. 12 (2002)

[文献書誌] 水野信哉, 他: "Annual Review 腎臓"中外医学社. 11 (2002)

[文献書誌] 別所一彦, 他: "遺伝子医学"メディカルドゥ. 7 (2002)

[文献書誌] 別所一彦, 他: "実験医学増刊"羊土社. 9 (2002)

[文献書誌] 角 智行, 他: "生化学"日本生化学学会. 6 (2002)

[文献書誌] 松本邦夫, 他: "日経サイエンス"日本経済新聞社. 12 (2002)

[文献書誌] 坂巻靖, 他: "The Lung Perspective"メディカルレビュー社. 8 (2002)

[文献書誌] 久場敬司, 他: "実験医学増刊"羊土社. 8 (2002)

2002 年度実績報告書

中村敏一大阪大学, 医学系研究科, 教授 (00049397)

[文献書誌] 角智行, 他: "生化学"日本生化学学会. 6 (2002)